KRAS under attack: recent advances in targeted therapies involving G12C inhibitors and XPO1 inhibition

KRAS is one of the most frequently mutated oncogenes, playing a critical role in several lethal cancers such as colorectal (5–10%), lung (20–30%) and pancreas (approximately 95%). Mutations in KRAS are usually associated with a poor response to chemotherapy (1) and may predispose to lung or brain metastases (2).

KRAS functions as a membrane-localized binary switch alternating between an inactive, guanosine diphosphate (GDP)-bound state and an active, guanosine triphosphate (GTP)-bound conformation, thereby controlling signal transduction. In non-small cell lung cancer (NSCLC), the most prevalent mutation of KRAS is G12C, which is located at the allosteric regulatory site and is predominantly associated with heavy smoking, whereas mutations such as G12D are mostly observed in non-smokers (3). Currently, two targeted substances—sotorasib and adagrasib—are approved for second-line treatment that directly block KRAS in its inactive state. Both agents are covalently specific for G12C; however, neither represents an optimal clinical solution. Anyhow, given an almost four-decade spanning effort trying to target the undruggable KRAS, oncologists can at least utilize an additional arrow in the quiver. Most KRAS variants are located in hotspot codons 12, 13 and 61 with slightly different biochemical characteristics. Although in close proximity to one another, different KRAS single nucleotide variants (SNV) affecting distinct codons may exert specific interactions with their effectors and different sensitivities to targeted therapies, hindering efforts to generating effective direct- (pan-) KRAS inhibitors (4). Since direct targeting of KRAS mutations remains challenging, other ways are being explored. These include indirect approaches like KRAS degraders, interrupting membrane translocation, inhibiting downstream targets like mitogen-activated protein kinase (MEK), inhibiting KRAS binding partners [i.e., guanine nucleotide exchange factors (GEFs)] like son of sevenless (SOS), and others.

In this respect, the phase 1 interim results by von Itzstein et al. (5) are particularly intriguing, as exportin-1 (XPO1) inhibition appears to circumvent the limitations associated with both direct and indirect KRAS pathway inhibition. Exportin-1 is a crucial shuttle protein, ensuring export of >200 cargo proteins that contain a nuclear export signal through the nuclear membrane (6). Inhibition of XPO1 can lead to nuclear retention of tumor suppressors, including tumor protein 53 (p53). KRAS-mutated cancer cells seem to be particularly sensitive to XPO1 inhibition (7). Mitchell et al. report a positive effect of selinexor in metastatic lung cancer across all KRAS mutations, but this benefit is not observed in tumors harboring wildtype TP53. Recently, a similar correlation had been observed in ovarian cancer, since only the TP53wt/microsatellite stability (MSS)/proficient mismatch repair (pMMR) subgroup responded to selinexor. It was proposed that functional integrity of p53 may be required to potentiate the effect of selinexor. However, a confounding effect regarding the prognostically poor TP53-mutated cancers cannot be excluded (8). In NSCLC, XPO1 can be mutated or amplified (~0.5%) and whether this may have an impact on selinexor binding remains to be seen (9).

About 30% of lung adenocarcinomas carry a KRAS mutation, and about half of those are TP53 wildtype, leaving a target group for selinexor of about 15%. Certain mutational constellations have been described as long-term responders to mono-immunotherapy, including KRAS G12C, programmed death-ligand 1 (PD-L1) >50%, TP53 mutated; however, in the end, only a low percentage of patients are affected by such favorably biomarker constellations and powerful therapies are urgently needed for less favorable profiles. From a diagnostic perspective, KRAS and TP53 mutations are now standard in all commercial and lab-developed assays, both amplicon- and hybrid capture-based next-generation sequencing (NGS) assays. The KRAS gene is relatively short (six exons), so full coverage by NGS is not associated with a significant increase in cost or effort. TP53 is larger by number of exons and since it confers a commonly mutated tumor suppressor gene, it should be included in full length into NGS assays to detect all mutations, since they might be clinically relevant. In an increasingly complex biomarker environment, single-gene assays are limited by nature and should not be applied. A growing list of clinically relevant co-mutations (including KEAP1, STK11, and others) must be considered for treatment stratification by the oncologist. NGS provides this basis and can also be utilized for liquid biopsy testing. Selinexor is the first-in-class XPO1 inhibitor and is already approved by the Food and Drug Administration (FDA) for the treatment of relapsed and refractory multiple myeloma and for relapsed diffuse large B-cell lymphoma, demonstrating efficacy in these difficult-to-treat malignancies. Recently, long-term survival updates (4 years) were published from the phase 3 SIENDO trial, which compared selinexor with placebo in patients with stage IV or recurrent endometrial cancer (EC) who received remission after chemotherapy (10). In this trial, the median progression-free survival (PFS) for TP53 wildtype patients treated with selinexor compared with placebo was 28.4 versus 5.2 months; however, KRAS mutations are rare in EC and were not stratified in this study. Nonetheless, selinexor—alone or in combination—may provide a valuable treatment option in the future, especially for tumors carrying KRAS mutations beyond G12C. As of yet, there is sparse data on potential resistance mechanisms upon selinexor treatment. However, in vitro tumor models have described increased nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activity leading to selinexor resistance. Other potential resistance mechanisms include mutations in XPO1 and upregulation of transcription factor E2 promoter-binding factor 1 (E2F1) (11). For KRAS G12C mutated tumors, sotorasib (12) and adagrasib (13) were approved a few years ago for second-line treatment of metastatic NSCLC. Next-generation KRAS G12C inhibitors [e.g., MK-1084 (14), olomorasib (15)] are currently undergoing clinical evaluation and it remains to be seen how these substances will compete with other KRAS-targeted drugs. In the meantime, sotorasib (16), adagrasib (17) and other KRAS G12C inhibitors (18) are being evaluated as first-line treatment in the palliative setting in combination with chemo- or immuno therapy.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the Editorial Office, Translational Lung Cancer Research. The article has undergone external peer review.

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-665/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-2025-665/coif). J.H.F. received lecture fees from AstraZeneca, Roche and Sanofi; and fees for attending an advisory board from Roche. W.M.B. received honoraria for lectures, presentation, speakers bureaus, manuscript writing or educational events from AstraZeneca, Boehringer, Novartis, MSD, BMS, Lilly, Pfizer and Roche; received support for attending meetings and/or travel from Boehringer, Roche and AstraZeneca; participated on a data safety monitoring board or an advisory board on Astra Zeneca, Boehringer, Novartis, MSD, Lilly Pharma, BMS, and Roche; and received equipment, material, drugs, medical writing, gifts or other services from Boehringer (for medical writing). The other 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.

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