Novel LZTR1 germline mutation as a mechanism of resistance to osimertinib in EGFR-mutated lung adenocarcinoma: a case report

Introduction

Lung cancer is the leading cause of cancer-related deaths in the United States with approximately 340 deaths per day, almost 2.5 times more than colorectal cancer (1). Globally, depending on region, between 12.8% and 49.1% of patients with non-small cell lung cancer (NSCLC) harbor an epidermal growth factor receptor (EGFR) gene mutation (2). Although EGFR tyrosine kinase inhibitors (TKIs) provide significant clinical benefit to these patients, resistance eventually occurs via genetic and nongenetic mechanisms (3). There are few known de novo EGFR TKI resistance mechanisms. Here we present a patient with initial stage IIIA (T1b cN2 M0) adenocarcinoma of the lung, with confirmed EGFR exon 19 mutation (c.2236–2250del) with potential resistance to TKIs due to her leucine-zipper-like transcriptional regulator-1 (LZTR1) c.1653C>G variant. While LZTR1 mutations have been associated with EGFR resistance preclinically, to our knowledge, this is the first report of a patient with an LZTR1 germline mutation who had rapid progression on EGFR TKI. We present this case in accordance with the CARE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-723/rc).

Case presentation

A 52-year-old female former smoker with a past medical history of hypertension, autoimmune glomerulonephritis, and asthma, presented to urgent care with hemoptysis. A chest computed tomography (CT) showed a spiculated opacity measuring 1.1 cm × 1.1 cm in right middle lobe (RML) of the lung, in addition to a large right subcarinal lymph node measuring 2.6 cm × 1.7 cm, and a right hilar lymph node measuring 1.7 cm × 0.9 cm. Subsequent positron emission tomography (PET)-CT showed a hypermetabolic 1.1 cm RML nodule measuring up to 2.4 standardized uptake value (SUV), a poorly visualized right hilar lymph node with hypermetabolic activity measuring 7.2 SUV, and a 1.3 cm subcarinal lymph node with an SUV of 10 SUV. A magnetic resonance imaging (MRI) of the brain showed no evidence of intracranial metastatic disease. Of note, mediastinal staging was not done at the time of initial diagnosis. She was diagnosed with stage IIIA (T1b cN2 M0) adenocarcinoma of the lung (Figure 1). She reported a 10-pack-year smoking history and quit approximately 15 years prior to the diagnosis. Tumor analysis via clinical commercial Clinical Laboratory Improvement Amendments (CLIA)-certified next-generation sequencing (NGS) test was pursued as part of standard of care, identifying an EGFR exon 19 deletion (c.2236–2250del; p.E746_A70del), CCNE1 amplification, LZTR1 (c.1653C>G; p.Y551*), PIK3CA (c.3140A>G; p.H1047R), RB1 (c.2330del; p.777Lfs*33), TP53 (c.278del; p.L93Rfs*30), tumor mutational burden (TMB) (low), microsatellite instability (MSI) (stable), programmed death-ligand 1 (PD-L1) 22C3 0% (Table 1). No family history of cancer was reported. She was treated with concurrent radiation therapy for a total of 6,000 cGy in 30 fractions, with weekly cisplatin (30 mg) and etoposide (50 mg), completing six cycles. She then transferred care to City of Hope. All procedures performed in this study were in accordance with the ethical standards of the City of Hope Institutional Review Board and with the Declaration of Helsinki (as revised in 2013). Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Figure 1 Patient’s clinical timeline. RML, right middle lobe; R, right; LN, lymph node; Bx, biopsy; LUAD, lung adenocarcinoma; EGFR, epidermal growth factor receptor; ChemoXRT, chemoradiation therapy; w, with; Carbo, carboplatin; LZTR1, leucine-zipper-like transcriptional regulator-1; PD, progressive disease; IV, intravenous; TKI, tyrosine kinase inhibitor; Amp., amplification; TMB, tumor mutation burden; Mut/Mb, mutations per megabase; MSI, microsatellite instability; PD-L1, programmed death-ligand 1; Atezo, atezolizumab; Bev, bevacizumab; SRS, stereotactic radiosurgery; RUL, right upper lobe; WBRT, whole-brain radiation therapy.

Restaging scans showed resolution of the subcarinal and right hilar adenopathy with a decrease in the right lower lobe pulmonary nodule. She elected to participate in a Precision Medicine Study at City of Hope which includes germline genetic testing via commercial CLIA-certified test revealing a pathogenic LZTR1 mutation (c.1653C>G; p.Y551*) (Table 1). Given prior radiation treatment, surgical resection was not pursued. Considering the actionable EGFR mutation and her history of autoimmune glomerulonephritis, maintenance therapy with osimertinib, an EGFR TKI, was planned in lieu of single agent immunotherapy. Prior to initiating adjuvant osimertinib, an additional CT of the chest showed diseased progression evidenced by multiple hepatic and bony lesions. Given the disease progression, systemic therapy with carboplatin [area under the curve (AUC) 5], pemetrexed (500 mg/m²) every 3 weeks, and osimertinib (80 mg daily) was initiated. Restaging PET-CT and MRI of the abdomen, following four cycles of carboplatin and pemetrexed, showed an increase in the size and number of liver lesions. A liver biopsy was performed and demonstrated the lesion was consistent with poorly differentiated carcinoma and metastatic pulmonary adenocarcinoma. Tumor profiling of the liver lesion was also obtained, which showed the pathogenic germline LZTR1 variant at an allele frequency of 68% and the previously noted EGFR exon 19 deletion at a frequency of 24%. Consequently, treatment was escalated to carboplatin (AUC 5), paclitaxel (175 mg/m²), bevacizumab (15 mg/kg), and atezolizumab (1,200 mg) every 3 weeks. Despite aggressive treatment with carboplatin, paclitaxel, bevacizumab, and atezolizumab, she continued to progress with disease metastasis to the brain, lung, and liver. She was treated with stereotactic radiosurgery (SRS) to the brain lesion and switched her systemic treatment to ramucirumab (10 mg/kg) plus docetaxel (37.5 mg/m², dose reduced by 50% for drug-drug interaction with concomitant medication posaconazole) every 3 weeks. Multiple new brain lesions were noted and whole brain radiotherapy was initiated upon progression. The patient and family transitioned to comfort care. Shortly after the transition, the patient deceased.

Discussion

In the precision oncology approach, the implications of germline pathogenic variants continue to extend beyond its traditional role in early cancer detection and risk reducing options. Germline pathogenic variants are reported to cause an earlier age at cancer diagnosis and our patient was diagnosed at an earlier age of 52 years old (4). Preliminary evidence also shows that germline molecular testing guidelines need to be expanded as germline mutations have been detected in lung cancer patients without smoking history or family history of cancer (4,5). A case report of a young lung cancer patient with maternally inherited BRCA2 germline variant showed efficacy of olaparib in combination with pembrolizumab (6). More recently, a phase II study investigating the role of germline mutations in advanced solid tumors showed efficacy of BRCA1/2 inhibitor olaparib (7). Taken together, this suggests that germline mutation variants are more common in lung cancer than previously thought and may be a potential avenue for future therapeutic targets.

Somatic mutations in LZTR1 gene mutations have been reported in various cancers including glioblastoma, hepatocellular, esophagogastric, and colorectal cancers. Proposed as a tumor suppressor gene, LZTR1 gene encodes leucine zipper-like transcription regulator 1 protein containing Kelch-BTB-BACK domains. LZTR1 protein functions as a substrate adaptor of CUL3 (8). Kelch domain is required for substrate recognition while the BTB-BACK domain interacts with CUL3. The role of LZTR1 and its target substrates in human cancers is not clearly understood. It is thought to be involved in ubiquitination and degradation of endogenous KRAS and mitogen-activated protein kinase (MAPK) pathway activation (9). LZTR1 has been shown to function as a “RAS killer protein” and recent preclinical studies showed that LZTR1 may regulate the growth and invasion of lung cancer cells through RAS/MAPK signaling (9-12).

Recently, Ko et al. [2023] uncovered two oncogenic receptor tyrosine kinase (RTK), EGFR and AXL as novel protein substrates of LZTR1 using multiple unbiased proteomics screens (13). Ubiquitination by LZTR1 led to lysosomal mediated degradation of EGFR and AXL proteins and signaling downregulation. The presence of somatic and germline mutations of LZTR1-mutant tumors was shown to cause EGFR and AXL accumulation and deregulated signaling, which may mediate TKI resistance. The study demonstrated that EGFR and AXL accumulated at significantly higher levels in schwannomas from individuals with germline mutations of LZTR1 compared to those with sporadic schwannomas and SMARCB1-related schwannomas. By analyzing transcriptomic profiles from RNA-sequencing (RNA-seq) data of schwannoma patients with LZTR1 and those without LZTR1, the study also found that EGF-dependent RTK activation and RTK activities are significantly higher in LZTR1 mutation group. Through in vitro and in vivo experiments, the group revealed that when treated with a single RTK inhibitor, the persistent activity of EGFR or AXL is sufficient to sustain survival and growth of LZTR1-mutated cells. Hence, it was proposed that co-inhibition of both EGFR and AXL would provide a more effective treatment opportunity in reducing tumor growth and improving survival compared with single-drug treatments in LZTR1 mutant tumors. In our patient, an LZTR1 pathogenic mutation Y551* was detected prior to initiation of osimertinib-chemotherapy combination treatment and the patient rapidly progressed within 4 months as compared to progression-free survival (PFS) 27.9 months in FLAURA2 study (14). While evidence of LZTR1 germline mutation resistance remains scarce the detection of a pathogenic germline mutation suggests that it may have affected this patient’s rapid progression. However, impact due to the interaction between chemotherapy and osimertinib or other resistance mechanisms cannot be fully excluded.

Conclusions

In EGFR-mutated NSCLC patients, the presence of a concurrent germline LZTR1 mutation may indicate resistance and serve as a potential negative biomarker for predicting efficacy of osimertinib. This study was limited as it is a single EGFR patient report with a concomitant LZTR1 germline mutation. While EGFR mutations are common in lung cancer germline mutation testing is not performed on all patients and it is difficult to ascertain the frequency of this co-mutation in all patients. Nevertheless, our findings are concordant with the literature regarding a possible EGFR-LZTR1 resistance relationship. Future preclinical and clinical studies are required to determine the mechanism of resistance and concomitant therapeutic options, as suggested by Ko et al. (13).

Acknowledgments

The authors thank the patient and her family. The patient gave written informed consent authorizing the use and disclosure of de-identified data for publication. We would also like to thank City of Hope nurses and clinical staff for their dedication to taking care of patients.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-723/rc

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-723/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-723/coif). The authors have no conflicts of interest 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. All procedures performed in this study were in accordance with the ethical standards of the City of Hope Institutional Review Board and with the Declaration of Helsinki (as revised in 2013). Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

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/.

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