Clinical translation for targeting DNA damage repair in non-small cell lung cancer: a review

Introduction

DNA damage and genomic instability in non-small cell lung cancer (NSCLC)

In recent decades, lung cancer (LC) research has shown significant advancements in screening, diagnosis, and treatment, thanks to the rapid development of technologies such as low-dose computed tomography (LDCT) scan, minimal invasive techniques (1), stereotactic ablative radiotherapy (SABR), new targeted therapy, and new immunotherapy. These advancements have improved the survival rate of LC patients by 56% in men and 32% in women (2). Despite this progress, LC remains the leading cause of cancer death, with an estimated 2.2 million new cases and 1.8 million deaths recorded in 2020 (3).

LC has two major pathological subtypes: the predominant NSCLC (85%) and small cell lung cancer (SCLC; 15%). NSCLC can be further divided into lung adenocarcinoma (LUAD; 50%), squamous cell carcinoma (LUSC; 40–30%), and large cell carcinoma (LCC; 20–10%) respectively.

The stability of the genome is paramount to the survival and reproduction of all cells. Friedberg et al. reported that human body is subjected to between 10,000 and 1,000,000 instances of DNA damage per day (4). DNA damage caused by endogenous (for example free radicals) (5,6) or exogenous (for example ionizing radiation) factors (7-9) can lead to genome instability and diseases such as cancer. DNA double strand breaks (DSBs) are the most severe type of damage, as accumulation of incorrectly repaired or unrepaired DSBs can cause mutation, genomic instability, or induce cell death (10).

LC generally exhibits a distinct genomic profile compared with other tumors, with high somatic mutational burden (11). Smoking is the main cause of LC, accounting for 90% of cases, however, approximately 20% of newly-diagnosed LUAD cases are attributed to non- or light-smokers in developed countries now. Smokers have higher somatic mutational burden than non-smokers (12) and smokers carry additional genomic instability processes that are likely to contribute to tumor progression (13). NSCLC primary tumors exhibit high genomic diversity with heterogenous tumor driver mutations present that clones may not all carry the same mutation making it very difficult for the patient to benefit from targeted therapies.

DNA damage is repaired by specific cellular pathways during normal cell cycle. When DNA damage fails to be repaired or excised, the mutations will eventually trigger carcinogenesis. For instance, epidermal growth factor receptor (EGFR) exon 19 deletion corrected with decreased expression of ERCC1 impacts ERCC1 foci formation in response to DNA cross-link damage, contributing to DNA damage repair (DDR) deficiency (14). Germline variants of ataxia-telangiectasia mutated (ATM), tumor suppressor 53 protein (TP53), breast cancer 2 (BRCA2), EGFR, and Parkinson’s Disease-Associated protein 2 (PARK2) had been linked to cancer risk in Mendelian disorders (15). Chromosomal instability may cause tumor heterogeneity and drug resistance, and epigenetic silencing of DNA repair genes may promote tumorigenesis. For instance, over 60% NSCLC cases present aneuploidy. Chromosomal instability elevates in the NSCLC patients with ROS1 fusion treated with crizotinib (16). In addition to mutations, epigenetic silencing of DNA repair genes may promote tumorigenesis. The Aurora kinase (AURK) family is involved in mitosis and chromosomal segregation. Abnormalities in AURK proteins can be associated with genomic instability. Overexpression of AURKA (17-22) or AURKB (23-25) was corrected with poor prognosis of overall survival (OS) in NSCLC. Some researches revealed that AURKA and AURAB was associated with resistance of EGFR-TKI (26-28), chemotherapy (29-31) and/or radiotherapy (17,32,33) in LC in pre-clinical models.

Target therapy and immune checkpoint inhibitors (ICIs)-based treatment with/without chemotherapy have been widely used in NSCLC. Despite a number of inhibitors had been developed for targeting EGFR, ALK, ROS1, KRAS, MET, NTRK, HER2 and RET, LUSC and LCC rarely present mutations in tyrosine kinase receptors compared with LUAD.

DNA repair in NSCLC

Various DNA repair pathways, including direct reversal repair (DRR), base excision repair (BER), nucleotide excision repair (NER), mismatch repair (MMR), non-homologous end joining (NHEJ), homologous recombination (HR), and interchain crosslinking repair, can circumvent DNA damage.

DNA damage caused by various agents such as alkylation, oxidation, ultra-violet (UV) radiation, and cross-linking requires different repair mechanisms. The mechanism of DRR is involved in reversing the O-alkylated DNA damage caused by methylguanine methyl transferase (MGMT) (34). DRR also removes photolesions caused by UV radiation with DNA-photolyase (35,36). The activity of the DNA repair enzyme 8-oxoguanine DNA N-glycosylase (OGG), is associated with LC (37). BER can repair small base lesion damage such as the damage on 8-oxo-7,8-dihydro-2’-deoxyguanosine (8-OHdG) by radicals with DNA glycosylase, apurinic/apyrimidinic (AP) endonuclease, DNA polymerase and DNA ligase (38,39). The BER pathway is one component of the larger DDR system that repairs and works with other pathways.

The NER mechanism is responsible for repairing Cyclobutane pyrimidine dimers (CPD) and pyrimidine-pyrimidone (6-4) photoproducts [(6-4)PP] caused by UV radiation (38). There is a group of proteins (XPA-XPG, RPA, CSA, CSB, ERCC6 and RAD23B, etc.) that are involved in NER process (40). In LC, Lys751Gln (41) and ERCC2-rs13181 (42) polymorphism pose significant risk in allele, heterozygote, and dominant comparisons.

MMR corrects base mismatch pairs and small loops. MMR does it with MSH2, MSH6, MLH1, PCNA and RPA proteins by identifying the site of the insertion-deletion loop, removing the lesion site and replacing it with newly synthesized DNA (43). These repair mechanisms have been associated with different cancers, including LC. MMR deficiency (dMMR) leads to multiple mutations at repetitive DNA sequence stretches known as microsatellite instability (MSI). MSI-high/dMMR varies widely among different cancer types. In LUAD, it accounted for 0.53–1% while 0.6% in LUSC respectively (44).

Currently, ICIs had been approved for MSI-high/dMMR in solid tumors. The deficiency expression of MSH2 or MLH1 in LUAD has been associated with resistance to immunotherapy (44). A study had reported MSI-high/dMMR group demonstrated greater survival and responded to ICIs in NSCLC (45). The high tumor mutation burden (TMB) corrected with DDR gene mutations and mutations of DNA methyltransferase 3a (DNMT3A) and DDR pathway-related genes increased tumor-infiltrating lymphocytes (46) and were important predictive markers for OS in NSCLC (47).

While BER, NER and MMR fix single-strand break (SSB) repair, DSB repair requires HR, NHEJ and alternative end joining (alt-EJ) pathways. Homologous recombinant repair (HRR) is a complicated process pathway to repair DSB in S and G2 phases of the cell cycle. HRR faithfully duplicates the genome by providing the critical support for DNA replication and telomere maintenance due to its dependence on the existence of sister chromatids. For instance, in HRR, RAD51 is the core mechanism of RAD51 filament formation and DNA strand invasion. This repair also plays a role in the repair of DNA interstrand crosslinks (ICLs) with the collaboration of NER through involvement of ERCC1 endonuclease (48). The NHEJ pathway is essential for repairing DSBs throughout the cell cycle, while alt-EJ assists in repairing the residual DSBs when NHEJ and HR are unavailable. The tumor suppressor gene TP53 plays an important role in cell cycle regulation, and frequent TP53 mutations may cause DNA damage, leading to tumorigenesis and metastasis. The repair of interstrand crosslinking requires Fanconi anemia (FA) active proteins. It was reported that 49.6% NSCLC patients identified having deleterious DDR mutations and associated with improved clinical outcomes of ICIs (49). The understanding of these repair mechanisms can help in the development of more effective therapies for LC and other cancers.

Targeting DDR pathways can be exploited as a means of cancer therapy. In the following sections, we will discuss several DDR inhibitors including their application as monotherapy or in combination with chemotherapy, radiotherapy and immunotherapy and demonstrate their current landscape of research in NSCLC for clinical use. We also discuss potential predictive biomarkers of response in the pre-clinical or clinical trials. The list of DDR inhibitors is presented in Table 1.

Strategies for targeting the DDR in NSCLC

Single agent activity and determinants of sensitivity

Poly (ADP-ribose) polymerase (PARP) inhibitor

The PARP is a family of nuclear protein enzymes that are activated upon binding to damage DNA and involved in DDR. Inhibition of PARP impair repair of SSBs that leads to synthetic lethality in HR-deficient (such as deleterious of BRCA1/2) cells which unable accurately repair DSBs. Several PARP inhibitors have been approved by FDA against different cancers with or without HR-deficient such as olaparib, niraparib, rucaparib, talazoparib (50). The development of veliparib is not very successful, not very successful as it resulted in less PARP trapping and was inactive (51).

Studies on PARP1/2 inhibitor as a monotherapy had purported it as a novel therapeutic strategy for NSCLC cells with ERCC1-deficient (52), or deficiencies in HR genes [loss of function of BRCA1 and BRCA2, ATM and elevated RAD54L expression (53), or lysine methyl transferase 2C/D (KMT2C/D) mutation (54), or ELF3 expression (55), or AXL expression (56)]. PPP2R2A is commonly downregulated in NSCLC cells, and loss of PPP2R2A may serve as a marker to predict sensitivity to PARP inhibitor (57).

In advanced NSCLC, PARP inhibitor shows limited antitumor activity. Two trials tested olaparib maintenance in NSCLC patients with chemosensitivity; compared with placebo, a trend toward longer progression-free survival (PFS; 16.6 vs. 12.0 months) and OS (59.4 vs. 31.3 months) (58); compared with standard of care (SoC), no significant PFS (2.7 vs. 2.7 months) and OS (14.3 vs. 14.1 months) differences were observed (59). In the SAFIR02-lung trial, 2.1% (8/379) patients with pathogenic BRCA1/2 mutation indicated limited sensitivity to olaparib (60). Antitumor activity of niraparib single-agent was noted in NSCLC in the phase I dose-escalation trial; tumor shrinkage occurred in all two enrolled NSCLC patients, one BRCA2 mutation carrier had stable disease (SD) for 175 days, the other previous heavily treated patient maintained SD for 316 days (61). Talazoparib failed to show sufficient level of efficacy with 4% (1/24) overall response rate (ORR) and 54% (13/24) disease control rate (DCR) in LUSC with HRR deficiency [alteration in ATM, ataxia telangiectasia and Rad3 related protein (ATR), BRCA1, BRCA2, or PALB2] in a phase 2 Lung-MAP subgroup S1400G (62). In another subgroup S1900A of Lung-MAP, with rucaparib, the study chose stage IV NSCLC patients with high genomic loss of heterozygosity (LOH) and/or BRCA1/2 mutated and progression on or after platinum base chemotherapy and/or programmed death (ligand) 1 (PD1/PD-L1) antibody; the study showed activity with 7% ORR (4 patients: 3 BRCA1/2-mutated and 1 LOH-high) and 7.8 months OS (63) respectively.

In these EGFR mutated LC patients, low BRCA1 mRNA levels were associated with longer PFS in erlotinib-treated patients and acquired resistance of EGFR-TKI treatment could promote the sensitivity of PARP inhibitors (64). A case report showed that olaparib with dacomitinib could prolong the survival of NSCLC patients with leptomeningeal metastasis (65). When compared combination of gefitinib and olaparib with solely gefitinib, the combination did not provide significant benefit (10.9 vs. 12.8 months) in a phase II trial (66); this could be attributed to high BRCA1 mRNA expression and low mRNA expression of CtIP (67). The phase I study of niraparib in combination with osimertinib in EGFR-mutated advanced LC is underway (NCT03891615) (Table 2).

AZD5305 is a second generation, highly selective PARP1 inhibitor. It is currently in phase I/II trial as monotherapy and in combination with other treatment in solid tumors which including NSCLC (Table 2).

ATR inhibitors

ATR and ATM are the members of the phosphatidylinositol 3-kinases-related kinases (PIKK) family of serine/threonine protein kinases. ATR is one of the two apical regulators in the DDR pathway of active cellular response includes cell cycle checkpoints and DNA repair. ATM share similar function and structure with ATR.

ATR and ATM are prime targets of DDR inhibitors. ATR inhibitor has demonstrated therapeutic potential activity in cancer treatment.

Several compounds targeting ATR are moving to clinical trial stage. M6620 (VX970/Berzosertib/VE822) was well tolerated, with preliminary antitumor responses observed in a patient with metastasis colorectal cancer (mCRC) harboring ATM loss and AT-rich interactive domain-containing protein 1A (ARID1A) mutation reached complete response (CR) and 29 months PFS (68). Ceralasertib (AZD6738) monotherapy was well tolerated and resulted in confirmed partial response (PR) and a high proportion of prolonged SD in advanced tumors of PATRIOT trial (69). BAY1895344 (Elimusertib, NSC#810486) was tolerable and had antitumor activity in patients with various advanced solid tumors with certain DDR deficiency including ATM loss (70). M4344 (YX-803) is currently in phase I single-agent or in combination with carboplatin study to determine the safety and maximum tolerated dose (NCT02278250). The trial of M1774 as monotherapy and in combination with niraparib is recruiting the patients with metastatic or locally advanced unresectable solid tumors including a group to explore the biomarker of loss of function mutations in the genes for ARID1A, ATM, or alpha thalassemia/mental retardation syndrome X-linked (ATRX) and/or (death-domain-associated protein) DAXX (NCT04170153). There are no ongoing trials in NSCLC with ATR inhibitor monotherapy, but in combination with other anti-cancer treatments, M1774, M6620 and AZD6738 are currently on the development of phase II/III studies as listed in Table 2.

AURK inhibitor

AURK belongs to a family (known as AURKA, AURKB and AURKC) of highly conserved serine and threonine kinases that function as key regulators of the mitosis process. AURKA and AURKB constitutes potential targets in NSCLC. Several agents inhibited to AURK have been developed, AURKA inhibitors (TC-A2317, alisertib/MLN8237, ENMD2076, MK5108, VIC1911, LY3295668, TAS-119), AURKB inhibitors (Quercetin, GSK 1070916, barasertib/AZD1152) and pan-AURK inhibitors (danusertib/PHA739358, AMG900, AT9283).

MK-5108 had proven anticancer activity in NSCLC in vitro as monotherapy or in combination with chemotherapies (71). AT9283 is a multi-targeted kinase inhibitor of tyrosine and serine/threonine kinases including Aurora A and B, JAK2, and Abl. AT9283 alone indicated well tolerated, antiproliferative and apoptotic activity and demonstrated SD (≥6 months) in esophageal cancer (n=1), NSCLC (n=2) and colorectal cancer (CRC; n=1) in a phase I dose escalation study (72).

Danusertib (PHA-739358) is a small-molecule pan-aurora kinase inhibitor. A trial reported that danusertib single-agent reached marginal antitumor activity, the progression free rate at 4 months (PFR-4) was 10.4% (5/48) in NSCLC (all histotypes), 16.1% (5/31) in LUSC and 0% (0/14) in SCLC (73). Another phase II study evaluated the efficacy of danusertib alone in advanced treated NSCLC in a Simon two-stage design; 3/19 patients were PFR-4 in stage I, the antitumor activity was better in LUSC better than non-squamous NSCLC (nsqNSCLC) (PFS: 6.4 vs. 2.2 months, OS: 10.6 vs. 7.6 months); 5/31 evaluable squamous patients were PFR-4 in stage II (74).

Tanaka et al. (75) discovered AURKB inhibitors as potent enhancers of osimertinib-induced apoptosis and combined EGFR-TKI and AURKB inhibitor could overcome EGFR-TKI resistance. Alisertib (MLN8237) treatment restored the susceptibility of resistant cells to EGFR-TKIs and partially reversed the epithelial-mesenchymal transition (EMT) process (76). The phase II trial tested single agent alisertib in patients had undergone two or fewer previous cytotoxic regimens; it was noted that the objective response in ten of 48 participants with SCLC and one of 23 patients with NSCLC (77). In patients with recurrent or metastatic EGFR wild-type NSCLC, the combination of erlotinib and alisertib was tolerable and effective (with one patient was PR >10 cycles and 5 patients were SD) in a phase I/II study (78). The combination of alisertib and osimertinib was an acceptable safety profile and established 10% (1/10) ORR in patients with advanced EGFR mutated LUAD who experienced progression on osimertinib monotherapy (79). In a phase 1b study of osimertinib plus alisertib or sapanisertib for osimertinib-resistant EGFR-mutant (EGFRm) NSCLC, osimertinib plus alisertib (n=20) showed median PFS was 1.9 months, ORR (5%) and DCR (40%) (80). There are two ongoing clinical trials using AURKA inhibitors VIC-1911 or LY3295668 in combination with osimertinib in EGFR mutant NSCLC (NCT05489731) (NCT05017025).

AURKA amplification is reported in NSCLC, and AURKA signaling may mediate adaptive resistance to KRAS inhibition. A study to research VIC-1911 combine with sotorasib for treatment of KRAS mutant NSCLC is ongoing (NCT05374538).

Apurinic/apyrimidinic endonuclease 1 (APE1) inhibitor

Human APE1 is an essential BER protein that is known to be processing of potentially cytotoxic a basic DNA damage site. The overexpression of APE1 was associated with DNA repair capacity and poor survival in solid tumors (81). APE1 could serve as a potent target of antitumor drugs and several APE1 inhibitors have been developed. There are three types of APE1 inhibitors, including APE1 nuclease activity inhibitor (such as, methoxyamine/TRC-102, lucanthone), APE1 redox activity inhibitor (E3330/APX3330) and inhibitors of the APE1/nucleophosmin (gossypol/AT-101).

APE1 inhibitors induced DNA damage, apoptosis, pyroptosis, and necroptosis in NSCLC cell line A549 and NCI-H460 and impeded cancer progression in NCI-H460 mouse model (82). E3330 (APX3330) is highly selective inhibitor of apurinic/APE1/redox factor-1 (Ref-1). The anti-tumor effect of E3330 had been demonstrated in preclinical model in NSCLC (83). CRT0044876, a selective APE1 endonuclease inhibitor, inhibited the AP endonuclease, 3’-phosphodiesterase, and 3’-phosphatase activities of APE1. CRT0044876 showed no cytoxic effect in either NSCLC cell line A549 or NCI-H460 (82).

Overexpression APE1 promoted chemotherapy and EGFR-TKI resistance in NSCLC (84). Pre-clinical models suggested that AT-101 might serve a promise drug candidate for overcoming EGFR-TKIs resistance in H1975 cells harboring EGFR^L858R/T790M (85). A phase II trial of erlotinib and AT-101 in advanced EGFR-mutated NSCLC patients found 1 PR, 1 minor response (MR) and 3 SD in the enrolled six patients (NCT00988169).

DNA-dependent protein kinase catalytic subunit (DNA-PKcs) inhibitor

DNA-PK is a member PIKK family, which consists of a DNA-PKcs and a regulatory heterodimer Ku (Ku70/Ku80). DNA-PK plays a key role in repair of DSBs via NHEJ and it also involves in many other cellular processes. Reduced DNA-PK repair was associated with the risk of LC.

AZD7648, a highly specific and potent DNA-PK inhibitor, had anti-tumor activity in A549 NSCLC cell lines and xenograft models derived from LCs (86). The best ORR of nedisertib (peposertib, M3814, MSC2490484A) was SD in a phase I trial including two NSCLC patients (87). XRD-0394 is a dual kinase inhibitor of both ATM gene and DNA-PK. CC-115, inhibition of mTOR kinase and DNA-PK, was tested in vitro across a panel of 123 cancer cell lines including 39 LC cell lines and it potently inhibits proliferation and induces apoptosis in many cancer cell lines (88). In phase I trial, CC-115 showed clinical activity in endometrial carcinoma (CR, n=1, >4 years), head and neck squamous cell carcinoma (HNSCC), Ewing sarcoma, glioblastoma multiforme, castration-resistant prostate cancer (CRPC), and chronic lymphocytic leukemia (CLL) (PR, n=2 and SD, n=4), but it was found to cause apoptosis in NSCLC (n=1) (89).

In addition, as PIKKs have similar sequence to phosphatidylinositol-3 kinases (PI3Ks), the development of these inhibitors can base on small molecule inhibitors of PI3K. LY3023414 (samotolisib), a dual PI3K/mammalian target of rapamycin (mTOR) inhibitor, displayed PR of a patient with endometrial cancer harboring PIK3R1 and Phosphatase and tensin homolog (PTEN) truncating mutations and 13 (28%) additional patients had a decrease in target lesions by up to 30%, but the all 3 patients of NSCLC were no response in the first-in human phase I trial (90). XL765 (voxtalisib, SAR245409) is a new chemical entity that inhibits the kinases PI3K and mTOR. No partial response reported with XL765 and erlotinib in NSCLC patients treated with EGFR inhibitor previously in phase I trial (91).

WEE1 inhibitor

WEE1 inhibitor, is a selective inhibitor of the WEE1 kinase, a key regulator of the G2/M and S phase cell-cycle checkpoints.

AZD1775 (adavosertib) is a highly selective, small molecule inhibitor of protein kinase Wee1 which allows cells to with a deregulated G1 checkpoint to progress. AZD1775 single agent demonstrated efficacy and well tolerated in mouse xenograft model in TP53-mutated subgroup of KRAS-mutated NSCLC (92). There are 61 clinical trials registered in CTG (https://clinicaltrials.gov) about AZD1775 from 2008. AZD1775 showed its antitumor activities especially in these cancers harbor DNA damage, such as mCRC with RAS and TP53 mutated (93). However, in a biomarker-driven phase 2 umbrella trial for patients with recurrent SCLC, no patient had partial response for ADZ1775 alone in 47 patients with different biomarkers in 4 groups (94). The scientists have not found the effective strategy to launch this product whatever the predictive biomarkers for response or in combination with other anti-cancer agents.

Another four compounds ZN-c3 (NCT04158336), Debio0123 (NCT03968653), IMP7068 (NCT04768868) and SY-4835 (NCT05291182) are currently in phase I trial in solid tumors which including NSCLC (Table 2).

CHK1 and CHK2 inhibitor

The cell cycles regulatory kinase, CHK1 and CHK2, coordinate with DDR pathways and immediate targets of the kinases ATM/ATR. CHK1/2 inhibitors have development for a long time, numerous compounds step towards slowly because of the complexity of optimizing dose and schedule selection and major questions mark over the efficacy. The dual CHK1/CHK2 inhibitor XL-844 (EXEL-9844) was terminated trials in 2008. PF0047736 was terminated to develop in 2012 in advanced cancers. SNS-032 (BMS-387032), a potent inhibitor of cyclin-dependent kinases 2, 7 and 9, demonstrated limited clinical activity in solid tumors. Prexasertib (LY2606368) demonstrated activity in different cancers, including 2 (4.4%) patients with squamous cell cancers (SCCs) (95), 4 (20%) patients with SCCs (96), 3 (5.2%) patients with SCLC (97) and one (11.1%) BRCA wild type triple negative breast cancer (TNBC) (98), however, one NSCLC patient had no response (95).

Researchers consider how to combine CHK1 inhibitors with other compounds or to find proper biomarkers to get more encouraging data. In pre-clinical model, the low levels of POLA1, POLE, and POLE2 protein expression in NSCLC and CRC cells corrected with CHK1 inhibitor sensitivity (99). UCN-01 (7-hydroxystaurosporine), the first CHK1/CHK2 inhibitor, contributed the antitumor activity in vitro and in vivo using A549 human LUAD cell line (100) and enhance the effective of radiation in cells with diminished TP53 activity (101,102). CHK1 expression in LUADs corrected with poor tumor differentiation and worse patient level and could be a predictive marker for CHK1 inhibitor (MK-8776) sensitivity in vitro study (103). Two patients (6.7%) showed partial response (melanoma and cholangiocarcinoma) in MK8776 monotherapy or in combination with gemcitabine phase I trial, however, one LUAD only have 1.43 months PFS (104).

Combinations with chemotherapy agents

In chemotherapy, cytotoxic drugs distort the chemical structure of DNA leading to inhibition of normal DNA replication. It makes strong rationale to combine DDR inhibitors with chemotherapy to enhance the DNA-damaging effect in cancer cells.

PARP inhibitor with chemotherapy

The combination of DDR inhibitors (such as PARP inhibitor) in selected HR-deficient tumors cause synthetic lethality, lead to genomic instability and cell death (105). Mechanistic studies indicated that PARP inhibitor plus cisplatin could lead to sustained DSBs, prolonged G2/M cell cycle arrest and more pronounced apoptosis preferentially in NSCLC cells with low ERCC1 expression (106), or PTEN deficient (107). Pre-clinical studies demonstrated antitumor efficacy of PARP inhibitor adding in different chemotherapy agents in NSCLC (108). In combination of veliparib and carboplatin/paclitaxel (CP) confirmed safety and preliminary efficacy with 55% (6/11) ORR in a phase I Japanese NSCLC cohort (109). In the following phase II trial of untreated advanced NSCLC, the veliparib-CP group showed favorable trend in ORR, PFS and OS vs. CP alone [PFS: 5.8 vs. 4.2 months, hazard ratio (HR) =0.72, P=0.17; OS: 11.7 vs. 9.1 months, HR =0.80, P=0.27] in all evaluable patients; patients with squamous histology had better outcomes (PFS: HR =0.54, P=0.098; OS: HR =0.73, P=0.24) (110). However, no therapeutic benefit of adding veliparib to first line chemotherapy in phase III trial, but risk of death was decreased by 34% in the LP521 population (110), and history of recent smoking was most predictive factor for veliparib-CP (111). In another phase III trial, there was no significant improvement of OS with veliparib plus chemotherapy in patients with nsqNSCLC, but improved OS in the LP52+ subgroup (112).

ATR inhibitor with chemotherapy

ATM loss by immunohistochemistry with ab32420 antibody was found in 41% (61/147) cases in LUAD cells and suggested to be a predictive biomarker for ATR inhibitor with cisplatin (113). A phase I study, with AZD6738- carboplatin, observed two PRs with low ATM or SLFN11 protein expression and 53% (18/34) SD patients; unconfirmed PR was found in a local advanced LUAD with four cycles of prior treatment (114).

Four (8.3%) patients (non-previously received gemcitabine) achieved PR with berzosertib and gemcitabine including a patient present with LUAD with no response of prior multiple chemotherapies (115). In the following phase Ib trial, berzosertib with gemcitabine in advanced and pre-treated NSCLC, four patients reached PR (4/38, ORR: 10.5%) and 18 patients had SD; in the exploratory cohort, ORR was 30% (3/10) in high LOH and 11% in low LOH, 33% (2/6) in high TMB, 12.5% (2/16) in intermediated TMB and 0% (0/3) in low TMB (116).

Testing the addition of BAY1895344 to chemotherapy for advance solid tumors is ongoing (NCT04491942), which is listed in Table 2.

APE1 inhibitor with chemotherapy

The phase I study published that 15 out of 25 patients with TRC-102 and pemetrexed evaluate SD or better, including LUSC (n=3) and nsqNSCLC (n=1) (117). Two clinical trials indicated that TRC-102 with temozolomide had anti-tumor activities in advanced solid tumor, with PR in a pancreatic neuroendocrine tumor (PNET) and prolonged SD in a NSCLC patient (5.5 months) (118), and PR (n=4, 1 NSCLC, 2 OCs, 1 CRC) (119).

WEE1 inhibitor with chemotherapy

WEE1 inhibition with TP53 mutation can disrupt both G1/S and G2/M, resulting in synthetic lethality and enhancing chemotherapy cytotoxicity. A phase II study of AZD1775 and carboplatin/pemetrexed in 1^st line metastatic nsqNSCLC presented 4 (29%) patients reached PR (one patient with AZD1775 alone for one year) and one patient had TP53 mutation. Another phase II study of AZD1775 plus docetaxel in recurrent NSCLC showed 3 (9%) patients evaluated PR (120).

Some clinical trials use WEE1 inhibitor, but its clinical development hampered higher grade 3 toxicities when added to standard treatments and no effective predictive biomarkers. There are ongoing trials conducting WEE1 inhibitors with other agents, such as chemotherapy, radiation, PARP/ATR inhibitor (NCT02513563, NCT0333084, NCT02511795), anti-PD-1/PD-L1 inhibitor, which are listed in Table 2.

CHK1/2 inhibitor with chemotherapy

Cells may remain viable as a result of upregulation of commentary mechanism with CHK1/2 inhibitor alone and make more susceptible to extrinsic DNA damage, which cause the interest of combination.

LY2603618 (rabusertib), a small molecule selective inhibitor CHK1 inhibitor, may enhance the effects of antimetabolites. LY2603618 with pemetrexed- cisplatin demonstrated that median PFS was significantly longer (4.7 vs. 1.5 months, P=0.022) in phase II study in patient with advanced cancers (121). With treatment GDC-0575 (ARRY-0575, RG774) and gemcitabine, four patients achieved confirmed partial responses with GDC-0575, including one NSCLC (593+ days on study), two sarcomas and TNBC with TP53 mutation (122).

Combinations with radiotherapy and/or chemoradiotherapy (CRT)

Radiotherapy can cause targeted DNA damage, which leads to the combination of DDR inhibitors and/or chemotherapy had been considered to ongoing clinical research. Most advanced NSCLC patients may have brain metastasis and radiation therapy has been an available tool in that kind of patients, which causes the strategy about the combination of DDR inhibitors and whole brain radiation therapy (WBRT).

The result of phase I study was encouraging safety and preliminary efficacy of veliparib plus WBRT in NSCLC with brain metastases (123), regrettably, no statistically significant differences in OS, intracranial response rate, and time to progression between the treatment arms were observed in the phase II randomization trial (124). Inhibition of AZD6738 could improve radiotherapy in preclinical models of NSCLC (125). A parallel dose-escalation study of AZD6738 combined with palliative radiotherapy in solid tumors is underway (NCT02223923). These data will provide the basis to leverage the potential radio-sensitization properties of a DDR inhibitor in combination with radiation in a variety of therapeutic settings.

Two phase I studies evaluate PRAP inhibitors plus CRT in patients with stage III NSCLC; Veliparib-CRT demonstrated acceptable safety and antitumor activity with an PFS of 19.6 months (126). A dose-finding study followed by a phase II randomization trial of CRT with or without veliparib (SWOG 1206); PFS was not difference between the two arms, while the OS was improved at 1 year 89% and 54%, respectively (127). The combination strategy was proved well tolerated and encouraging response with 20% (3/15) CR, 80% (12/15) PR and 49% of 2-year PFS rate in stage III nsqNSCLC (128) in the following phase I trial.

Combinations with other molecular targeted agents

DDR inhibitor-DDR inhibitor combination

Targeting enzymes in the same pathway also appears to have a synthetically lethal effect. Combination with different DDR inhibitors can induce synthetic lethality and also overcome acquired resistance to single agent.

As these mutations (such as BRCA1, BRCA2, ATM) alter the HRR pathway, there is increased reliance on other DDR pathways. ATR inhibitors overcame the bypass of BRCA1/2 in fork protection and PARP inhibitor resistance of BRCA-deficient cancers cells (129). Studies disclosed that combination of PARP inhibitor and ATR inhibitor induced death for ATM-deficiency cells of LUAD (130). Tumor reduction was observed in breast, prostate, pancreatic and ampullary cancers in AZD6738-olaparib group in a phase I trial (131). The signal of activity was seen with ceralasertib plus olaparib in recurrent platinum-resistant OC with BRCA1 mutation (132). In the pre-clinical models, KRAS-mutated NSCLC caused the increased levels of DNA damage and replication stress, which provided that inhibition of DDR was a promising strategy for olaparib plus AZD1775 (133). AZD7648 potentiated the activity of olaparib in xenograft and PDX models in NSCLC (134).

Some studies demonstrated replication fork arrest, ssDNA accumulation, replication collapse and synthetic lethal interaction between ATR inhibitor and other target inhibitors. The potential benefit of combination ATR inhibitor (VE-821) and CHK1 inhibitor (AZD7762) was seen in H460 lung tumor xenografts (135). PPP2R2A deficiency provided a biomarker to treat NSCLC with ATR and CHK1 inhibitor in pre-clinical study (136). The study confirmed the dependency on p53 mutation and ATM function for sensitivity to ATR inhibition by treating p53-mutated NSCLC cells with ATR inhibitor (VE-821) and ATM inhibitor (KU55933) (137). The effect of WEE1 inhibitor and ATR inhibitor was observed in NSCLC cell line (138).

Combination of other target agents

Some actionable oncoproteins can directly or indirectly regulate DDR and cell cycle checkpoint pathways, raising possibility of combination strategy with DDR inhibitors and other target agents.

PARP inhibitors have a strong synergistic interaction with type I protein arginine methyltransferase (PRMT) inhibition. Methylated p53 re-activation and induction of massive apoptosis (PRIMA-1Met) (APR-246) strongly synergized with olaparib in NSCLC cell lines (139) and Methylthioadenosine phosphorylase (MTAP)-negative NSCLC and certain cancer cells were resistant to PARP inhibitors (140). DNA methyltransferase inhibitors (DNMTi) created a BRCAness phenotype through downregulating expression of HRR and NHEJ genes, leaded to combinatorial PARP inhibitor and DNMTi therapy robustly sensitize NSCLC cells to ionizing radiation in vitro and in vivo (141). Bloom syndrome protein (BLM) helicase inhibitor (ML216) with PARP inhibitor improved the radiosensitivity of olaparib resistant NSCLC cell (142).

A phase 1b study, the Notch inhibitor Crenigacestat (LY3039478) in combination with LY3023414 in patients with advanced solid tumors, demonstrated poorly tolerated and response (0% ORR and 18.8% DCR) (143). In metastatic LUSC, LY3023414 vs. necitumumab vs. LY3023414 plus necitumumab exhibited significant benefit with event-free survival (EFS; 14.2 and 32.4 vs. 38.9 days) (144). LY3214996 (ERK1/2 inhibitor) plus LY3023414 and additive abemaciclib (CDK4/6 inhibitor) resulted in synergistic inhibition of tumor growth in PDX models of RAS-mutant LC (145).

However, these combination of doublet inhibitors are still in early exploratory status, the overlapping toxicity creates a whole new challenges of dose selection.

Combinations with immunotherapy

ICIs which target PD-1 and PD-L1 can enable the immune system to recognize and target cancer cells. Over recent decade, ICIs with single agent or combination of other therapy has dramatically expanded for the treatment of LC from neoadjuvant to last line. However, ICIs vary in their activity across different cancer types. Several biomarkers are associated with increase ICI response are PD-L1 expression, TMB, MSI or MMR-deficient. It is also explored that alteration of DDR genes related to high TMB and response of ICIs improvement. Unlike targeting genes mutation in cancer cells, the immune environment is complex, which lead future research shift to immune response effectiveness of combination therapy rather than identification biomarkers. Cancer causing genomic instability induce changes in the tumor environment and stimulate the generation of neoantigens on cancer cells, increasing the tumor response to immunotherapy and suggesting an effective therapeutic strategy to combine DDR inhibitors and immunotherapy.

Pre-clinical trial demonstrated PARP inhibitor potentiated IFN-γ-induced PD-L1 expression in NSCLC cell lines, enhanced in ERCC1-deficient contexts, promoted cellular immune response (146). Veliparib combined with nivolumab and platinum doublet CT was tolerated and had promising antitumor activity (confirmed objective response rate was 40%, and best ORR was 64%) in patients with advanced NSCLC in phase I dose escalation study (147). Olaparib-durvalumab indicated an acceptance toxicity and response in breast cancers (148) and mCRPC in the two phase II trials (149). Olaparib plus PD-1/PD-L1 inhibitor demonstrated response in two NSCLC patients with germline BRCA2 S497* (150) or BRCA2 G25085 (151). In the phase 2 JASPER trial, Niraparib-pembrolizumab as first line therapy showed clinical activity; 56.3% (9/16) ORR and 8.4 months PFS was found in cohort 1 [tumor proportion score (TPS) ≥50%]; 20% (4/20) ORR and 4.2 months PFS was discovered in cohort 2 (TPS 1–49%) in advanced NSCLC (152).

As PARP inhibitor plus immunotherapy shows promising therapeutic strategy in NSCLC, ongoing investigations are underway to evaluate the efficacy and safety. A phase I/II trial test rucaparib-pembrolizumab as maintenance therapy in stage IV nsqNSCLC after treatment of carboplatin, pemetrexed, and pembrolizumab (NCT03559049). A phase III trial treat pembrolizumab with concurrent chemoradiation therapy followed by pembrolizumab with or without olaparib in stage III NSCLC (NCT04380636) and a phase II trial compare SoC vs. olaparib-durvalumab in relapsed stage III NSCLC pretreated with CRT and durvalumab (NCT05568212). The phase III ZEAL-1L study is to compare the efficacy and safety of niraparib-pembrolizumab as maintenance therapy vs. placebo-pembrolizumab in patients who had SD or response to pembrolizumab plus platinum-based first-line induction chemotherapy for advanced NSCLC without known driver mutation (NCT04475939). A phase II study take talazoparib-avelumab in stage IV or recurrent nsqNSCLC with pathogenic STK11 mutation (LUNG-MAP Sub-Study) (NCT04173507). Please refer Table 2 for ongoing trial in LC.

Besides PARP inhibitors, the ATR inhibitors in combination with ICIs have been in clinical development. In a phase 2 trial, AZD6738-durvalumab had promising antitumor activity among patients with metastatic melanoma who had failed ICIs therapy (153). Beyond melanoma, AZD6738-durvalumab in advanced NSCLC of D5330C00004 trial also published encouraging date; 1 CR and 3 PRs (2 confirmed and 1 unconfirmed) out of 21 patients were found in advanced NSCLC (n=3) and HNSCC (n=1) irrespective of PD-L1 expression (131). In HUDSON umbrella trial, AZD6738-durvalumab provided effective activity compared with durvalumab alone in ATM mutation tumors (n=18) with median ORR at 13.3% and a median PFS of 7.43 months and 100% of patients were followed through after 6 months (154).

Based on the previously studies result, more trials start to investigate the efficacy and safety of the combination of ATR inhibitors and immunotherapy (Table 2); a phase III study to evaluate AZD6738-durvalumab vs. docetaxel in advanced NSCLC progressed prior treatment (NCT05450692); AZD6738-durvalumab for advanced NSCLC patients with ICI resistance (NCT03833440); M1774 in combination with cemiplimab in nsqNSCLC (NCT05882734); testing the addition of berzosertib to carboplatin and gemcitabine and to pembrolizumab for advanced LUSC (NCT04216316).

It is also interesting to combine WEE1 inhibitor with immunotherapy. Antitumor activity was observed with a DCR for the overall cohort of 36% in a phase I study to investigate preliminary activity of AZD1775-durvalumab in patients with advanced solid tumors (155).

A phase II trial of TRC102 in combination of pemetrexed, cisplatin and radiation therapy followed by durvalumab in patients with stage III nsqNSCLC is underway (NCT05198830).

Conclusions

Genomic profiling helps identify promising DDR targets of NSCLC, such as PARP, ATR, CHK1, CHK2, WEE1, AURK, DNA-PK, APE1. Medicine targeting these proteins are in various phase of preclinical or clinical development within different cancer types. The first approved DDR inhibitor, PARP inhibitors, have been used in certain patients with BRCA mutated. However, few DDR inhibitors run into phase 3 trial in NSCLC. Single agents of some DDR inhibitors show antitumor activity in NSCLC but limited. To improve the outcome, predictive biomarkers should be developed to optimize the response and an improve understanding of primary and acquired resistance mechanisms. The combination strategy of DDR inhibitors is usually chemotherapy and/or radiotherapy, which can enhance the effects. Combination of other target agents have demonstrated clinical potential and some of them step into clinical trials. Genomic instability of NSCLC influences innate and acquired immunity. Combination of DDR inhibitor and immunotherapy would be one of the most attractive future areas of research in NSCLC. While combine DDR inhibitor with different agents, their interactions should be considered. The appropriate dosing and scheduling of each agent to minimize toxicity adverse events and maximize benefits is critical factor for optimizing outcomes. In conclusion, we believe that comprehensive preclinical research into biology of DDR and clinical study progress in the DDR target agents, will lead great advances in the near future.

Acknowledgments

The authors would like to express their sincere gratitude and acknowledgement to the Universiti Malaysia Sarawak (UNIMAS) for enabling this study to go ahead with provision of digital facilities during the COVID-19 pandemic lockdown and UNIMAS publication fee support.

Funding: None.

Footnote

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-23-742/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-23-742/coif). The authors have no conflicts of interests to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Rijavec E, Coco S, Genova C, et al. Liquid Biopsy in Non-Small Cell Lung Cancer: Highlights and Challenges. Cancers (Basel) 2019;12:17. [Crossref] [PubMed]
2. Siegel RL, Miller KD, Fuchs HE, et al. Cancer statistics, 2022. CA Cancer J Clin 2022;72:7-33. [Crossref] [PubMed]
3. Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 2021;71:209-49. [Crossref] [PubMed]
4. Friedberg EC. Fixing your damaged and incorrect genes. Singapore: World Scientific Publishing Co. Pte. Ltd., 2019.
5. Owiti NA, Nagel ZD, Engelward BP. Fluorescence Sheds Light on DNA Damage, DNA Repair, and Mutations. Trends Cancer 2021;7:240-8. [Crossref] [PubMed]
6. Gupta N, Verma K, Nalla S, et al. Free Radicals as a Double-Edged Sword: The Cancer Preventive and Therapeutic Roles of Curcumin. Molecules 2020;25:5390. [Crossref] [PubMed]
7. Mavragani IV, Nikitaki Z, Kalospyros SA, et al. Ionizing Radiation and Complex DNA Damage: From Prediction to Detection Challenges and Biological Significance. Cancers (Basel) 2019;11:1789. [Crossref] [PubMed]
8. Maremonti E, Brede DA, Olsen AK, et al. Ionizing radiation, genotoxic stress, and mitochondrial DNA copy-number variation in Caenorhabditis elegans: droplet digital PCR analysis. Mutat Res Genet Toxicol Environ Mutagen 2020;858-860:503277. [Crossref] [PubMed]
9. Pariset E, Malkani S, Cekanaviciute E, et al. Ionizing radiation-induced risks to the central nervous system and countermeasures in cellular and rodent models. Int J Radiat Biol 2021;97:S132-50. [Crossref] [PubMed]
10. Bröckelmann PJ, de Jong MRW, Jachimowicz RD. Targeting DNA Repair, Cell Cycle, and Tumor Microenvironment in B Cell Lymphoma. Cells 2020;9:2287. [Crossref] [PubMed]
11. Chalmers ZR, Connelly CF, Fabrizio D, et al. Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden. Genome Med 2017;9:34. [Crossref] [PubMed]
12. Govindan R, Ding L, Griffith M, et al. Genomic landscape of non-small cell lung cancer in smokers and never-smokers. Cell 2012;150:1121-34. [Crossref] [PubMed]
13. de Bruin EC, McGranahan N, Mitter R, et al. Spatial and temporal diversity in genomic instability processes defines lung cancer evolution. Science 2014;346:251-6. [Crossref] [PubMed]
14. Zhang L, Pradhan B, Guo L, et al. EGFR exon 19-deletion aberrantly regulate ERCC1 expression that may partly impaired DNA damage repair ability in non-small cell lung cancer. Thorac Cancer 2020;11:277-85. [Crossref] [PubMed]
15. Parry EM, Gable DL, Stanley SE, et al. Germline Mutations in DNA Repair Genes in Lung Adenocarcinoma. J Thorac Oncol 2017;12:1673-8. [Crossref] [PubMed]
16. Soca-Chafre G, Montiel-Dávalos A, Rosa-Velázquez IA, et al. Multiple Molecular Targets Associated with Genomic Instability in Lung Cancer. Int J Genomics 2019;2019:9584504. [Crossref] [PubMed]
17. Liu N, Wang YA, Sun Y, et al. Inhibition of Aurora A enhances radiosensitivity in selected lung cancer cell lines. Respir Res 2019;20:230. [Crossref] [PubMed]
18. Zhang MY, Liu XX, Li H, et al. Elevated mRNA Levels of AURKA, CDC20 and TPX2 are associated with poor prognosis of smoking related lung adenocarcinoma using bioinformatics analysis. Int J Med Sci 2018;15:1676-85. [Crossref] [PubMed]
19. Al-Khafaji ASK, Marcus MW, Davies MPA, et al. AURKA mRNA expression is an independent predictor of poor prognosis in patients with non-small cell lung cancer. Oncol Lett 2017;13:4463-8. [Crossref] [PubMed]
20. Schneider MA, Christopoulos P, Muley T, et al. AURKA, DLGAP5, TPX2, KIF11 and CKAP5: Five specific mitosis-associated genes correlate with poor prognosis for non-small cell lung cancer patients. Int J Oncol 2017;50:365-72. [Crossref] [PubMed]
21. Xu J, Yue CF, Zhou WH, et al. Aurora-A contributes to cisplatin resistance and lymphatic metastasis in non-small cell lung cancer and predicts poor prognosis. J Transl Med 2014;12:200. [Crossref] [PubMed]
22. Kuang P, Chen Z, Wang J, et al. Characterization of Aurora A and Its Impact on the Effect of Cisplatin-Based Chemotherapy in Patients with Non-Small Cell Lung Cancer. Transl Oncol 2017;10:367-77. [Crossref] [PubMed]
23. Takeshita M, Koga T, Takayama K, et al. Aurora-B overexpression is correlated with aneuploidy and poor prognosis in non-small cell lung cancer. Lung Cancer 2013;80:85-90. [Crossref] [PubMed]
24. Hayama S, Daigo Y, Yamabuki T, et al. Phosphorylation and activation of cell division cycle associated 8 by aurora kinase B plays a significant role in human lung carcinogenesis. Cancer Res 2007;67:4113-22. [Crossref] [PubMed]
25. Vischioni B, Oudejans JJ, Vos W, et al. Frequent overexpression of aurora B kinase, a novel drug target, in non-small cell lung carcinoma patients. Mol Cancer Ther 2006;5:2905-13. [Crossref] [PubMed]
26. Bertran-Alamillo J, Cattan V, Schoumacher M, et al. AURKB as a target in non-small cell lung cancer with acquired resistance to anti-EGFR therapy. Nat Commun 2019;10:1812. [Crossref] [PubMed]
27. Shah KN, Bhatt R, Rotow J, et al. Aurora kinase A drives the evolution of resistance to third-generation EGFR inhibitors in lung cancer. Nat Med 2019;25:111-8. [Crossref] [PubMed]
28. Wu CC, Yu CT, Chang GC, et al. Aurora-A promotes gefitinib resistance via a NF-κB signaling pathway in p53 knockdown lung cancer cells. Biochem Biophys Res Commun 2011;405:168-72. [Crossref] [PubMed]
29. Linardopoulos S. Aurora-A kinase regulates NF-kappaB activity: lessons from combination studies. J BUON 2007;12:S67-70.
30. Sun C, Chan F, Briassouli P, et al. Aurora kinase inhibition downregulates NF-kappaB and sensitises tumour cells to chemotherapeutic agents. Biochem Biophys Res Commun 2007;352:220-5. [Crossref] [PubMed]
31. Al-Khafaji AS, Davies MP, Risk JM, et al. Aurora B expression modulates paclitaxel response in non-small cell lung cancer. Br J Cancer 2017;116:592-9. [Crossref] [PubMed]
32. Orth M, Unger K, Schoetz U, et al. Taxane-mediated radiosensitization derives from chromosomal missegregation on tripolar mitotic spindles orchestrated by AURKA and TPX2. Oncogene 2018;37:52-62. [Crossref] [PubMed]
33. Liu JB, Hu L, Yang Z, et al. Aurora-A/NF-ĸB Signaling Is Associated With Radio-resistance in Human Lung Adenocarcinoma. Anticancer Res 2019;39:5991-8. [Crossref] [PubMed]
34. Soll JM, Sobol RW, Mosammaparast N. Regulation of DNA Alkylation Damage Repair: Lessons and Therapeutic Opportunities. Trends Biochem Sci 2017;42:206-18. [Crossref] [PubMed]
35. Kavakli IH, Ozturk N, Gul S. DNA repair by photolyases. Adv Protein Chem Struct Biol 2019;115:1-19. [Crossref] [PubMed]
36. Sancar A. Mechanisms of DNA Repair by Photolyase and Excision Nuclease (Nobel Lecture). Angew Chem Int Ed Engl 2016;55:8502-27. [Crossref] [PubMed]
37. Paz-Elizur T, Krupsky M, Blumenstein S, et al. DNA repair activity for oxidative damage and risk of lung cancer. J Natl Cancer Inst 2003;95:1312-9. [Crossref] [PubMed]
38. Vechtomova YL, Telegina TA, Buglak AA, et al. UV Radiation in DNA Damage and Repair Involving DNA-Photolyases and Cryptochromes. Biomedicines 2021;9:1564. [Crossref] [PubMed]
39. Robertson AB, Klungland A, Rognes T, et al. DNA repair in mammalian cells: Base excision repair: the long and short of it. Cell Mol Life Sci 2009;66:981-93. [Crossref] [PubMed]
40. Schärer OD. Nucleotide excision repair in eukaryotes. Cold Spring Harb Perspect Biol 2013;5:a012609. [Crossref] [PubMed]
41. Li W, Li K, Zhao L, et al. DNA repair pathway genes and lung cancer susceptibility: a meta-analysis. Gene 2014;538:361-5. [Crossref] [PubMed]
42. Li W, Zhang M, Huang C, et al. Genetic variants of DNA repair pathway genes on lung cancer risk. Pathol Res Pract 2019;215:152548. [Crossref] [PubMed]
43. Li Z, Pearlman AH, Hsieh P. DNA mismatch repair and the DNA damage response. DNA Repair (Amst) 2016;38:94-101. [Crossref] [PubMed]
44. Zhao P, Li L, Jiang X, et al. Mismatch repair deficiency/microsatellite instability-high as a predictor for anti-PD-1/PD-L1 immunotherapy efficacy. J Hematol Oncol 2019;12:54. [Crossref] [PubMed]
45. Olivares-Hernández A, Del Barco Morillo E, Parra Pérez C, et al. Influence of DNA Mismatch Repair (MMR) System in Survival and Response to Immune Checkpoint Inhibitors (ICIs) in Non-Small Cell Lung Cancer (NSCLC): Retrospective Analysis. Biomedicines 2022;10:360. [Crossref] [PubMed]
46. Chang L, Chang M, Chang HM, et al. Microsatellite Instability: A Predictive Biomarker for Cancer Immunotherapy. Appl Immunohistochem Mol Morphol 2018;26:e15-21. [Crossref] [PubMed]
47. Zhang H, Deng YM, Chen ZC, et al. Clinical significance of tumor mutation burden and DNA damage repair in advanced stage non-small cell lung cancer patients. Eur Rev Med Pharmacol Sci 2020;24:7664-72. [Crossref] [PubMed]
48. Heyza JR, Lei W, Watza D, et al. Identification and Characterization of Synthetic Viability with ERCC1 Deficiency in Response to Interstrand Crosslinks in Lung Cancer. Clin Cancer Res 2019;25:2523-36. [Crossref] [PubMed]
49. Ricciuti B, Recondo G, Spurr LF, et al. Impact of DNA Damage Response and Repair (DDR) Gene Mutations on Efficacy of PD-(L)1 Immune Checkpoint Inhibition in Non-Small Cell Lung Cancer. Clin Cancer Res 2020;26:4135-42. [Crossref] [PubMed]
50. Mateo J, Lord CJ, Serra V, et al. A decade of clinical development of PARP inhibitors in perspective. Ann Oncol 2019;30:1437-47. [Crossref] [PubMed]
51. Murai J, Huang SY, Das BB, et al. Trapping of PARP1 and PARP2 by Clinical PARP Inhibitors. Cancer Res 2012;72:5588-99. [Crossref] [PubMed]
52. Xie K, Ni X, Lv S, et al. Synergistic effects of olaparib combined with ERCC1 on the sensitivity of cisplatin in non-small cell lung cancer. Oncol Lett 2021;21:365. [Crossref] [PubMed]
53. Deraska PV, Reavis HD, Labe S, et al. Homologous recombination pathway-based biomarkers for treatment of non-small cell lung cancer with PARP inhibitors. Cancer Res 2017;77:abstr 4189.
54. Chang A, Liu L, Ashby JM, et al. Recruitment of KMT2C/MLL3 to DNA Damage Sites Mediates DNA Damage Responses and Regulates PARP Inhibitor Sensitivity in Cancer. Cancer Res 2021;81:3358-73. [Crossref] [PubMed]
55. Wang Y, Zuo M, Jin H, et al. Inhibition of ELF3 confers synthetic lethality of PARP inhibitor in non-small cell lung cancer. J Recept Signal Transduct Res 2021;41:304-11. [Crossref] [PubMed]
56. Balaji K, Vijayaraghavan S, Diao L, et al. AXL Inhibition Suppresses the DNA Damage Response and Sensitizes Cells to PARP Inhibition in Multiple Cancers. Mol Cancer Res 2017;15:45-58. [Crossref] [PubMed]
57. Kalev P, Simicek M, Vazquez I, et al. Loss of PPP2R2A inhibits homologous recombination DNA repair and predicts tumor sensitivity to PARP inhibition. Cancer Res 2012;72:6414-24. [Crossref] [PubMed]
58. Fennell DA, Lester JF, Danson S, et al. A randomized phase II trial of olaparib maintenance versus placebo monotherapy in patients with chemosensitive advanced non-small cell lung cancer. J Clin Oncol 2020;38:e21649.
59. Besse B, Karimi M, Tomasini P, et al. Maintenance targeted therapy compared to standard of care (SoC) in patients (pts) with metastatic non-small cell lung cancer (NSCLC): Results from the phase II randomized UNICANCER/IFCT1301- SAFIR02-LUNG intergroup trial. J Clin Oncol 2021;39:9095.
60. Barlesi F, Tomasini P, Karimi M, et al. Comprehensive Genome Profiling in Patients With Metastatic Non-Small Cell Lung Cancer: The Precision Medicine Phase II Randomized SAFIR02-Lung/IFCT 1301 Trial. Clin Cancer Res 2022;28:4018-26. [Crossref] [PubMed]
61. Sandhu SK, Schelman WR, Wilding G, et al. The poly(ADP-ribose) polymerase inhibitor niraparib (MK4827) in BRCA mutation carriers and patients with sporadic cancer: a phase 1 dose-escalation trial. Lancet Oncol 2013;14:882-92. [Crossref] [PubMed]
62. Owonikoko TK, Redman MW, Byers LA, et al. Phase 2 Study of Talazoparib in Patients With Homologous Recombination Repair-Deficient Squamous Cell Lung Cancer: Lung-MAP Substudy S1400G. Clin Lung Cancer 2021;22:187-194.e1. [Crossref] [PubMed]
63. Riess JW, Redman MW, Wheatley-Price P, et al. A phase II study of rucaparib in patients with high genomic LOH and/or BRCA 1/2 mutated stage IV non-small cell lung cancer (Lung-MAP Sub-Study, S1900A). J Clin Oncol 2021;39:9024.
64. Marcar L, Bardhan K, Gheorghiu L, et al. Acquired Resistance of EGFR-Mutated Lung Cancer to Tyrosine Kinase Inhibitor Treatment Promotes PARP Inhibitor Sensitivity. Cell Rep 2019;27:3422-3432.e4. [Crossref] [PubMed]
65. Zhang H, Wang Y, Wu H, et al. Olaparib Combined With Dacomitinib in Osimertinib-Resistant Brain and Leptomeningeal Metastases From Non-Small Cell Lung Cancer: A Case Report and Systematic Review. Front Oncol 2022;12:877279. [Crossref] [PubMed]
66. Garcia-Campelo R, Arrieta O, Massuti B, et al. Combination of gefitinib and olaparib versus gefitinib alone in EGFR mutant non-small-cell lung cancer (NSCLC): A multicenter, randomized phase II study (GOAL). Lung Cancer 2020;150:62-9. [Crossref] [PubMed]
67. Karachaliou N, Arrieta O, Giménez-Capitán A, et al. BRCA1 Expression and Outcome in Patients With EGFR-Mutant NSCLC Treated With Gefitinib Alone or in Combination With Olaparib. JTO Clin Res Rep 2021;2:100113. [Crossref] [PubMed]
68. Yap TA, O'Carrigan B, Penney MS, et al. Phase I Trial of First-in-Class ATR Inhibitor M6620 (VX-970) as Monotherapy or in Combination With Carboplatin in Patients With Advanced Solid Tumors. J Clin Oncol 2020;38:3195-204. [Crossref] [PubMed]
69. Dillon M, Guevara J, Mohammed K, et al. 450PD - A phase I study of ATR inhibitor, AZD6738, as monotherapy in advanced solid tumours (PATRIOT part A, B). Ann Oncol 2019;30:v165-6.
70. Yap TA, Tan DSP, Terbuch A, et al. First-in-Human Trial of the Oral Ataxia Telangiectasia and RAD3-Related (ATR) Inhibitor BAY 1895344 in Patients with Advanced Solid Tumors. Cancer Discov 2021;11:80-91. [Crossref] [PubMed]
71. Chinn DC, Holland WS, Mack PC. Anticancer activity of the Aurora A kinase inhibitor MK-5108 in non-small-cell lung cancer (NSCLC) in vitro as monotherapy and in combination with chemotherapies. J Cancer Res Clin Oncol 2014;140:1137-49. [Crossref] [PubMed]
72. Arkenau HT, Plummer R, Molife LR, et al. A phase I dose escalation study of AT9283, a small molecule inhibitor of aurora kinases, in patients with advanced solid malignancies. Ann Oncol 2012;23:1307-13. [Crossref] [PubMed]
73. Schöffski P, Besse B, Gauler T, et al. Efficacy and safety of biweekly i.v. administrations of the Aurora kinase inhibitor danusertib hydrochloride in independent cohorts of patients with advanced or metastatic breast, ovarian, colorectal, pancreatic, small-cell and non-small-cell lung cancer: a multi-tumour, multi-institutional phase II study. Ann Oncol 2015;26:598-607. [Crossref] [PubMed]
74. Gauler TC, Besse B, Novello S, et al. Phase II study of danusertib (D) in advanced/metastatic non-small cell lung cancers (NSCLC). J Clin Oncol 2013;31:e19138.
75. Tanaka K, Yu HA, Yang S, et al. Targeting Aurora B kinase prevents and overcomes resistance to EGFR inhibitors in lung cancer by enhancing BIM- and PUMA-mediated apoptosis. Cancer Cell 2021;39:1245-1261.e6. [Crossref] [PubMed]
76. Wang CY, Lee MH, Kao YR, et al. Alisertib inhibits migration and invasion of EGFR-TKI resistant cells by partially reversing the epithelial-mesenchymal transition. Biochim Biophys Acta Mol Cell Res 2021;1868:119016. [Crossref] [PubMed]
77. Melichar B, Adenis A, Lockhart AC, et al. Safety and activity of alisertib, an investigational aurora kinase A inhibitor, in patients with breast cancer, small-cell lung cancer, non-small-cell lung cancer, head and neck squamous-cell carcinoma, and gastro-oesophageal adenocarcinoma: a five-arm phase 2 study. Lancet Oncol 2015;16:395-405. [Crossref] [PubMed]
78. Godwin JL, Mehra R, Litwin S, et al. A phase I/II study of MLN-8237 (alisertib), an oral aurora kinase inhibitor, in combination with erlotinib in patients with recurrent or metastatic EGFR wild-type non-small cell lung cancer. J Clin Oncol 2016;34:e20588.
79. Blakely CM, Gubens MA, Allen GM, et al. Phase I study of the aurora kinase A inhibitor alisertib in combination with osimertinib in EGFR-mutant lung cancer. J Clin Oncol 2021;39:9074.
80. Elamin YY, Negrao MV, Fossella FV, et al. Results of a phase 1b study of osimertinib plus sapanisertib or alisertib for osimertinib-resistant, EGFR-mutant non–small cell lung cancer (NSCLC). J Clin Oncol 2022;40:9105.
81. Yuan CL, He F, Ye JZ, et al. APE1 overexpression is associated with poor survival in patients with solid tumors: a meta-analysis. Oncotarget 2017;8:59720-8. [Crossref] [PubMed]
82. Long K, Gu L, Li L, et al. Small-molecule inhibition of APE1 induces apoptosis, pyroptosis, and necroptosis in non-small cell lung cancer. Cell Death Dis 2021;12:503. [Crossref] [PubMed]
83. Manguinhas R, Fernandes AS, Costa JG, et al. Impact of the APE1 Redox Function Inhibitor E3330 in Non-small Cell Lung Cancer Cells Exposed to Cisplatin: Increased Cytotoxicity and Impairment of Cell Migration and Invasion. Antioxidants (Basel) 2020;9:550. [Crossref] [PubMed]
84. Yang X, Peng Y, Jiang X, et al. The regulatory role of APE1 in epithelial-to-mesenchymal transition and in determining EGFR-TKI responsiveness in non-small-cell lung cancer. Cancer Med 2018;7:4406-19. [Crossref] [PubMed]
85. Xu J, Zhu GY, Cao D, et al. Gossypol overcomes EGFR-TKIs resistance in non-small cell lung cancer cells by targeting YAP/TAZ and EGFR(L858R/T790M). Biomed Pharmacother 2019;115:108860. [Crossref] [PubMed]
86. Cadogan EB, Fok JH, Ramos-Montoya A, et al. AZD7648: A potent and selective inhibitor of DNA-PK with pharmacodynamic and monotherapy anti-tumor activity. Cancer Res 2019;79:abstr 3505.
87. Hwang I, Guan Z, Cao C, et al. Nanoparticles suppress fluid instabilities in the thermal drawing of ultralong nanowires. Nat Commun 2020;11:5932. [Crossref] [PubMed]
88. Tsuji T, Sapinoso LM, Tran T, et al. CC-115, a dual inhibitor of mTOR kinase and DNA-PK, blocks DNA damage repair pathways and selectively inhibits ATM-deficient cell growth in vitro. Oncotarget 2017;8:74688-702. [Crossref] [PubMed]
89. Munster P, Mita M, Mahipal A, et al. First-In-Human Phase I Study Of A Dual mTOR Kinase And DNA-PK Inhibitor (CC-115) In Advanced Malignancy. Cancer Manag Res 2019;11:10463-76. [Crossref] [PubMed]
90. Bendell JC, Varghese AM, Hyman DM, et al. A First-in-Human Phase 1 Study of LY3023414, an Oral PI3K/mTOR Dual Inhibitor, in Patients with Advanced Cancer. Clin Cancer Res 2018;24:3253-62. [Crossref] [PubMed]
91. Jänne PA, Cohen RB, Laird AD, et al. Phase I safety and pharmacokinetic study of the PI3K/mTOR inhibitor SAR245409 (XL765) in combination with erlotinib in patients with advanced solid tumors. J Thorac Oncol 2014;9:316-23. [Crossref] [PubMed]
92. Ku BM, Bae YH, Koh J, et al. Mutational status of TP53 defines the efficacy of Wee1 inhibitor AZD1775 in KRAS-mutant non-small cell lung cancer. Oncotarget 2017;8:67526-37. [Crossref] [PubMed]
93. Seligmann JF, Fisher DJ, Brown LC, et al. Inhibition of WEE1 Is Effective in TP53- and RAS-Mutant Metastatic Colorectal Cancer: A Randomized Trial (FOCUS4-C) Comparing Adavosertib (AZD1775) With Active Monitoring. J Clin Oncol 2021;39:3705-15. [Crossref] [PubMed]
94. Park S, Shim J, Mortimer PGS, et al. Biomarker-driven phase 2 umbrella trial study for patients with recurrent small cell lung cancer failing platinum-based chemotherapy. Cancer 2020;126:4002-12. [Crossref] [PubMed]
95. Hong D, Infante J, Janku F, et al. Phase I Study of LY2606368, a Checkpoint Kinase 1 Inhibitor, in Patients With Advanced Cancer. J Clin Oncol 2016;34:1764-71. [Crossref] [PubMed]
96. Hong DS, Moore K, Patel M, et al. Evaluation of Prexasertib, a Checkpoint Kinase 1 Inhibitor, in a Phase Ib Study of Patients with Squamous Cell Carcinoma. Clin Cancer Res 2018;24:3263-72. [Crossref] [PubMed]
97. Byers LA, Navarro A, Schaefer E, et al. A Phase II Trial of Prexasertib (LY2606368) in Patients With Extensive-Stage Small-Cell Lung Cancer. Clin Lung Cancer 2021;22:531-40. [Crossref] [PubMed]
98. Gatti-Mays ME, Karzai FH, Soltani SN, et al. A Phase II Single Arm Pilot Study of the CHK1 Inhibitor Prexasertib (LY2606368) in BRCA Wild-Type, Advanced Triple-Negative Breast Cancer. Oncologist 2020;25:1013-e1824. [Crossref] [PubMed]
99. Rogers RF, Walton MI, Cherry DL, et al. CHK1 Inhibition Is Synthetically Lethal with Loss of B-Family DNA Polymerase Function in Human Lung and Colorectal Cancer Cells. Cancer Res 2020;80:1735-47. [Crossref] [PubMed]
100. Kawakami K, Futami H, Takahara J, et al. UCN-01, 7-hydroxyl-staurosporine, inhibits kinase activity of cyclin-dependent kinases and reduces the phosphorylation of the retinoblastoma susceptibility gene product in A549 human lung cancer cell line. Biochem Biophys Res Commun 1996;219:778-83. [Crossref] [PubMed]
101. Mack PC, Jones AA, Gustafsson MH, et al. Enhancement of radiation cytotoxicity by UCN-01 in non-small cell lung carcinoma cells. Radiat Res 2004;162:623-34. [Crossref] [PubMed]
102. Xiao HH, Makeyev Y, Butler J, et al. 7-Hydroxystaurosporine (UCN-01) preferentially sensitizes cells with a disrupted TP53 to gamma radiation in lung cancer cell lines. Radiat Res 2002;158:84-93. [Crossref] [PubMed]
103. Grabauskiene S, Bergeron EJ, Chen G, et al. CHK1 levels correlate with sensitization to pemetrexed by CHK1 inhibitors in non-small cell lung cancer cells. Lung Cancer 2013;82:477-84. [Crossref] [PubMed]
104. Daud AI, Ashworth MT, Strosberg J, et al. Phase I dose-escalation trial of checkpoint kinase 1 inhibitor MK-8776 as monotherapy and in combination with gemcitabine in patients with advanced solid tumors. J Clin Oncol 2015;33:1060-6. [Crossref] [PubMed]
105. Lord CJ, Ashworth A. PARP inhibitors: Synthetic lethality in the clinic. Science 2017;355:1152-8. [Crossref] [PubMed]
106. Cheng H, Zhang Z, Borczuk A, et al. PARP inhibition selectively increases sensitivity to cisplatin in ERCC1-low non-small cell lung cancer cells. Carcinogenesis 2013;34:739-49. [Crossref] [PubMed]
107. Minami D, Takigawa N, Takeda H, et al. Synergistic effect of olaparib with combination of cisplatin on PTEN-deficient lung cancer cells. Mol Cancer Res 2013;11:140-8. [Crossref] [PubMed]
108. Stolzenburg LR, Ainsworth B, Riley-Gillis B, et al. Transcriptomics reveals in vivo efficacy of PARP inhibitor combinatorial synergy with platinum-based chemotherapy in human non-small cell lung carcinoma models. Oncotarget 2022;13:1-12. [Crossref] [PubMed]
109. Mizugaki H, Yamamoto N, Nokihara H, et al. A phase 1 study evaluating the pharmacokinetics and preliminary efficacy of veliparib (ABT-888) in combination with carboplatin/paclitaxel in Japanese subjects with non-small cell lung cancer (NSCLC). Cancer Chemother Pharmacol 2015;76:1063-72. [Crossref] [PubMed]
110. Ramalingam SS, Novello S, Guclu SZ, et al. Veliparib in Combination With Platinum-Based Chemotherapy for First-Line Treatment of Advanced Squamous Cell Lung Cancer: A Randomized, Multicenter Phase III Study. J Clin Oncol 2021;39:3633-44. [Crossref] [PubMed]
111. Reck M, Blais N, Juhasz E, et al. Smoking History Predicts Sensitivity to PARP Inhibitor Veliparib in Patients with Advanced Non-Small Cell Lung Cancer. J Thorac Oncol 2017;12:1098-108. [Crossref] [PubMed]
112. Govindan R, Lind M, Insa A, et al. Veliparib Plus Carboplatin and Paclitaxel Versus Investigator's Choice of Standard Chemotherapy in Patients With Advanced Non-Squamous Non-Small Cell Lung Cancer. Clin Lung Cancer 2022;23:214-25. [Crossref] [PubMed]
113. Villaruz LC, Jones H, Dacic S, et al. ATM protein is deficient in over 40% of lung adenocarcinomas. Oncotarget 2016;7:57714-25. [Crossref] [PubMed]
114. Yap TA, Krebs MG, Postel-Vinay S, et al. Ceralasertib (AZD6738), an Oral ATR Kinase Inhibitor, in Combination with Carboplatin in Patients with Advanced Solid Tumors: A Phase I Study. Clin Cancer Res 2021;27:5213-24. [Crossref] [PubMed]
115. Middleton MR, Dean E, Evans TRJ, et al. Phase 1 study of the ATR inhibitor berzosertib (formerly M6620, VX-970) combined with gemcitabine ± cisplatin in patients with advanced solid tumours. Br J Cancer 2021;125:510-9. [Crossref] [PubMed]
116. Plummer R, Dean E, Arkenau HT, et al. A phase 1b study evaluating the safety and preliminary efficacy of berzosertib in combination with gemcitabine in patients with advanced non-small cell lung cancer. Lung Cancer 2022;163:19-26. [Crossref] [PubMed]
117. Gordon MS, Rosen LS, Mendelson D, et al. A phase 1 study of TRC102, an inhibitor of base excision repair, and pemetrexed in patients with advanced solid tumors. Invest New Drugs 2013;31:714-23. [Crossref] [PubMed]
118. Eads JR, Krishnamurthi SS, Saltzman J, et al. Phase I clinical trial of temozolomide and methoxyamine (TRC-102), an inhibitor of base excision repair, in patients with advanced solid tumors. Invest New Drugs 2021;39:142-51. [Crossref] [PubMed]
119. Coyne GO, Kummar S, Meehan RS, et al. Phase I trial of TRC102 (methoxyamine HCl) in combination with temozolomide in patients with relapsed solid tumors and lymphomas. Oncotarget 2020;11:3959-71. [Crossref] [PubMed]
120. Spigel DR, Dakhil S, Beck JT, et al. Phase II studies of AZD1775, a WEE1 kinase inhibitor, and chemotherapy in non-small-cell lung cancer (NSCLC): Lead-in cohort results. Ann Oncol 2016;27:VI121.
121. Wehler T, Thomas M, Schumann C, et al. A randomized, phase 2 evaluation of the CHK1 inhibitor, LY2603618, administered in combination with pemetrexed and cisplatin in patients with advanced nonsquamous non-small cell lung cancer. Lung Cancer 2017;108:212-6. [Crossref] [PubMed]
122. Italiano A, Infante JR, Shapiro GI, et al. Phase I study of the checkpoint kinase 1 inhibitor GDC-0575 in combination with gemcitabine in patients with refractory solid tumors. Ann Oncol 2018;29:1304-11. [Crossref] [PubMed]
123. Mehta MP, Wang D, Wang F, et al. Veliparib in combination with whole brain radiation therapy in patients with brain metastases: results of a phase 1 study. J Neurooncol 2015;122:409-17. [Crossref] [PubMed]
124. Fan Y, Zhu X, Xu Y, et al. Cell-Cycle and DNA-Damage Response Pathway Is Involved in Leptomeningeal Metastasis of Non-Small Cell Lung Cancer. Clin Cancer Res 2018;24:209-16. [Crossref] [PubMed]
125. Dunne V, Ghita M, Small DM, et al. Inhibition of ataxia telangiectasia related-3 (ATR) improves therapeutic index in preclinical models of non-small cell lung cancer (NSCLC) radiotherapy. Radiother Oncol 2017;124:475-81. [Crossref] [PubMed]
126. Kozono DE, Stinchcombe TE, Salama JK, et al. Veliparib in combination with carboplatin/paclitaxel-based chemoradiotherapy in patients with stage III non-small cell lung cancer. Lung Cancer 2021;159:56-65. [Crossref] [PubMed]
127. Argiris A, Miao J, Cristea MC, et al. A Dose-finding Study Followed by a Phase II Randomized, Placebo-controlled Trial of Chemoradiotherapy With or Without Veliparib in Stage III Non-small-cell Lung Cancer: SWOG 1206 (8811). Clin Lung Cancer 2021;22:313-323.e1. [Crossref] [PubMed]
128. Biswas T, Dowlati A, Kunos C, et al. Base excision repair (BER) inhibitor TRC 102 (Methoxyamine) combined with pemetrexed (PEM)-based chemo-radiation (CRT) for locally advanced non-squamous non-small cell lung cancer (NS-NSCLC): Results of a phase I trial. J Clin Oncol 2020;38:9027.
129. Kim H, Xu H, George E, et al. Combining PARP with ATR inhibition overcomes PARP inhibitor and platinum resistance in ovarian cancer models. Nat Commun 2020;11:3726. [Crossref] [PubMed]
130. Jette NR, Radhamani S, Arthur G, et al. Combined poly-ADP ribose polymerase and ataxia-telangiectasia mutated/Rad3-related inhibition targets ataxia-telangiectasia mutated-deficient lung cancer cells. Br J Cancer 2019;121:600-10. [Crossref] [PubMed]
131. Krebs MG, Lopez J, El-Khoueiry A, et al. Phase I study of AZD6738, an inhibitor of ataxia telangiectasia Rad3-related (ATR), in combination with olaparib or durvalumab in patients (pts) with advanced solid cancers. Cancer Res 2018;78:abstr CT026.
132. Shah PD, Wethington SL, Pagan C, et al. Combination ATR and PARP Inhibitor (CAPRI): A phase 2 study of ceralasertib plus olaparib in patients with recurrent, platinum-resistant epithelial ovarian cancer. Gynecol Oncol 2021;163:246-53. [Crossref] [PubMed]
133. Parsels LA, Karnak D, Parsels JD, et al. PARP1 Trapping and DNA Replication Stress Enhance Radiosensitization with Combined WEE1 and PARP Inhibitors. Mol Cancer Res 2018;16:222-32. [Crossref] [PubMed]
134. Fok JHL, Ramos-Montoya A, Vazquez-Chantada M, et al. AZD7648 is a potent and selective DNA-PK inhibitor that enhances radiation, chemotherapy and olaparib activity. Nat Commun 2019;10:5065. [Crossref] [PubMed]
135. Sanjiv K, Hagenkort A, Calderón-Montaño JM, et al. Cancer-Specific Synthetic Lethality between ATR and CHK1 Kinase Activities. Cell Rep 2016;14:298-309. [Crossref] [PubMed]
136. Qiu Z, Fa P, Liu T, et al. A Genome-Wide Pooled shRNA Screen Identifies PPP2R2A as a Predictive Biomarker for the Response to ATR and CHK1 Inhibitors. Cancer Res 2020;80:3305-18. [Crossref] [PubMed]
137. Weber AM, Bokobza SM, Devery AM, et al. Combined ATM and ATR kinase inhibition selectively kills p53-mutated non-small cell lung cancer (NSCLC) cells. Mol Cancer Ther 2013;12:abstr B91.
138. Rødland GE, Hauge S, Hasvold G, et al. Differential Effects of Combined ATR/WEE1 Inhibition in Cancer Cells. Cancers (Basel) 2021;13:3790. [Crossref] [PubMed]
139. Deben C, Lardon F, Wouters A, et al. APR-246 (PRIMA-1(MET)) strongly synergizes with AZD2281 (olaparib) induced PARP inhibition to induce apoptosis in non-small cell lung cancer cell lines. Cancer Lett 2016;375:313-22. [Crossref] [PubMed]
140. Dominici C, Sgarioto N, Yu Z, et al. Synergistic effects of type I PRMT and PARP inhibitors against non-small cell lung cancer cells. Clin Epigenetics 2021;13:54. [Crossref] [PubMed]
141. Abbotts R, Topper MJ, Biondi C, et al. DNA methyltransferase inhibitors induce a BRCAness phenotype that sensitizes NSCLC to PARP inhibitor and ionizing radiation. Proc Natl Acad Sci U S A 2019;116:22609-18. [Crossref] [PubMed]
142. Kong Y, Xu C, Sun X, et al. BLM helicase inhibition synergizes with PARP inhibition to improve the radiosensitivity of olaparib resistant non-small cell lung cancer cells by inhibiting homologous recombination repair. Cancer Biol Med 2021;19:1150-71. [Crossref] [PubMed]
143. Azaro A, Massard C, Tap WD, et al. A phase 1b study of the Notch inhibitor crenigacestat (LY3039478) in combination with other anticancer target agents (taladegib, LY3023414, or abemaciclib) in patients with advanced or metastatic solid tumors. Invest New Drugs 2021;39:1089-98. [Crossref] [PubMed]
144. Melchior MA, Guo X, Donoho GP, et al. Antitumor efficacy of EGFR antibody necitumumab and dual PI3K/mTOR inhibitor (LY3023414) in preclinical tumor models. Mol Cancer Ther 2018;17:abstr B108.
145. Köhler J, Zhao Y, Li J, et al. ERK Inhibitor LY3214996-Based Treatment Strategies for RAS-Driven Lung Cancer. Mol Cancer Ther 2021;20:641-54. [Crossref] [PubMed]
146. Chabanon RM, Muirhead G, Krastev DB, et al. PARP inhibition enhances tumor cell-intrinsic immunity in ERCC1-deficient non-small cell lung cancer. J Clin Invest 2019;129:1211-28. [Crossref] [PubMed]
147. Clarke JM, Patel JD, Robert F, et al. Veliparib and nivolumab in combination with platinum doublet chemotherapy in patients with metastatic or advanced non-small cell lung cancer: A phase 1 dose escalation study. Lung Cancer 2021;161:180-8. [Crossref] [PubMed]
148. Domchek SM, Postel-Vinay S, Im SA, et al. Olaparib and durvalumab in patients with germline BRCA-mutated metastatic breast cancer (MEDIOLA): an open-label, multicentre, phase 1/2, basket study. Lancet Oncol 2020;21:1155-64. [Crossref] [PubMed]
149. Karzai F, VanderWeele D, Madan RA, et al. Activity of durvalumab plus olaparib in metastatic castration-resistant prostate cancer in men with and without DNA damage repair mutations. J Immunother Cancer 2018;6:141. [Crossref] [PubMed]
150. Waddington T, Mambetsariev I, Pharaon R, et al. Therapeutic Potential of Olaparib in Combination With Pembrolizumab in a Young Patient With a Maternally Inherited BRCA2 Germline Variant: A Research Report. Clin Lung Cancer 2021;22:e703-7. [Crossref] [PubMed]
151. Chen Z, Wang K, Zhao L, et al. BRCA2 mutation in advanced lung squamous cell carcinoma treated with Olaparib and a PD-1 inhibitor: a case report. Front Oncol 2023;13:1190100. [Crossref] [PubMed]
152. Ramalingam SS, Thara E, Awad MM, et al. JASPER: Phase 2 trial of first-line niraparib plus pembrolizumab in patients with advanced non-small cell lung cancer. Cancer 2022;128:65-74. [Crossref] [PubMed]
153. Kim R, Kwon M, An M, et al. Phase II study of ceralasertib (AZD6738) in combination with durvalumab in patients with advanced/metastatic melanoma who have failed prior anti-PD-1 therapy. Ann Oncol 2022;33:193-203. [Crossref] [PubMed]
154. Besse B, Awad M, Forde P, et al. OA07.08 HUDSON: An Open-Label, Multi-Drug, Biomarker-Directed, Phase II Platform Study in Patients with NSCLC, who Progressed on Anti-PD(L)1 Therapy. J Thorac Oncol 2021;16:S118-9.
155. Patel MR, Falchook GS, Wang JS, et al. Open-label, multicenter, phase I study to assess safety and tolerability of adavosertib plus durvalumab in patients with advanced solid tumors. J Clin Oncol 2019;37:2562.