A new therapeutic approach to KRAS mutant non-small cell lung cancer: the emerging role of exportin 1 inhibition

We thank Nagasaka et al. (1) and Falk et al. (2) for their thoughtful commentaries on our clinical trial of selinexor plus docetaxel in previously treated, advanced KRAS mutant non-small cell lung cancer (NSCLC) (3). Both groups highlight the many ongoing challenges of treating this subtype of lung cancer, which remains a major unmet clinical need. In our trial, we explored the potential role of exportin 1 (XPO1) inhibition as a novel strategy, finding that TP53 alteration status may correlate with efficacy. We appreciate the opportunity to expand on our trial’s key findings in the context of a changing field and to address implications for future research, including patient selection, trial design, and potential combination strategies.

Based on mechanistic rationale and preclinical data, our trial enrolled all types of NSCLC activating KRAS mutations, of which G12C generally represents only one-third. Importantly, therapeutic activity of selinexor, a selective inhibitor of nuclear export (SINE) that blocks the function of XPO1, was significantly greater in cases with wild-type TP53. Nagasaka et al. correctly emphasize the functional basis for this observation, as selinexor-induced nuclear retention of wild-type p53 facilitates the activation of pro-apoptotic pathways (e.g., PUMA, BAX) and cell cycle arrest (1). As Falk et al. discuss, similar patterns have been observed in other malignancies, such as endometrial cancer, where TP53 wild-type tumors respond better to XPO1 inhibition (4).

Determining whether such an association is prognostic or predictive can present a true challenge in drug development. Formally, it requires a randomized clinical trial that demonstrates a significant treatment-by-biomarker interaction. That is, the treatment effect differs significantly between biomarker-positive and biomarker-negative groups. In contrast, a prognostic marker has a consistent effect across treatment arms. As noted by Falk and colleagues, inactivating TP53 alterations are generally prognostic for poor outcomes in NSCLC. Whether they also have predictive capacity for XPO1 inhibition in KRAS mutant NSCLC remains a key question that is inadequately addressed by our single-arm, combination therapy trial. Although we sought preliminary insight into this consideration by focusing on improvement (decreased serum tumor markers, radiographic shrinkage) rather than disease control and progression, clearly further study is needed.

Both commentaries address how such future trials might be designed and implemented. Based on their preclinical studies demonstrating synergy, Nagasaka and colleagues suggest combinations of selinexor with KRAS G12C inhibitors for patients with KRAS G12C mutant NSCLC. Alternatively, they raise the possibility of investigating a five-drug regimen [chemoimmunotherapy (three drugs) plus KRAS G12C inhibitor (drug #4) plus selinexor (drug #5)] as a means of incorporating nuclear export inhibition into the first-line setting, potentially beyond TP53 mutant cases. Nagasaka also recognizes the importance of intensive biomarker testing such as routine serial cell-free DNA testing to identify sensitizing and resistance molecular features.

Before proceeding with multi-agent strategies as the focus of selinexor development, however, it may be worth investigating monotherapy for a few reasons. The first is tolerability. Even when administered weekly as single-agent therapy, selinexor requires an antiemetic regimen reminiscent of cisplatin premedication. It also causes fatigue, diarrhea, and myelosuppression. With the potential for overlapping toxicity with cytotoxic chemotherapy, immune checkpoint inhibitors, and KRAS inhibitors, one might imagine the challenges of administering or receiving such combinations. Second-generation nuclear export inhibitors, such as eltanexor, feature improved tolerability and may facilitate multi-drug regimens (1). The second reason is efficacy. Although our trial administered selinexor in combination with docetaxel, the following considerations are worth noting: (I) early decreases in surrogate markers of disease burden (serum LDH, alkaline phosphatase) and symptom improvement in the week between selinexor initiation and the first docetaxel dose; and (II) multiple trials have suggested that docetaxel has diminished efficacy in KRAS mutant compared to KRAS wild type NSCLC (5). If nuclear export inhibition may be driving the results observed in our recent trial, it may be reasonable to study single-agent therapy further. Indeed, only through such an approach will complex and costly correlative studies be truly interpretable.

That said, Nagasaki raises compelling reasons to consider combination trials. Preclinical work supports a model in which XPO1 inhibition promotes nuclear retention of tumor suppressors and regulatory proteins, thereby blunting adaptive transcriptional programs that contribute to KRAS TKI resistance (6,7). Further, the strategy of employing multiple active agents with varying mechanisms of action to counter resistance appears particularly attractive as (I) the field moves toward first-line treatment with targeted KRAS inhibition in combination with immunotherapy and/or chemotherapy, and (II) agents targeting non-G12C KRAS variants and pan-RAS TKIs advance (8).

As mentioned by Falk et al., comprehensive molecular profiling (including TP53 assessment and co-mutation status determination for relevant NSCLC genes such as STK11 and KEAP1) should be built into future trial eligibility and stratification. This is also important to correctly identify the approximately 15% of lung adenocarcinoma patients who harbor the KRAS mutant with TP53 wild type status that may benefit the most from XPO1 inhibition. Importantly, this prevalence resembles that of the most common genomically defined NSCLC populations such as EGFR mutations and certainly exceeds that of other actionable subsets, including KRAS G12C mutations (approximately 10%), ALK rearrangements (approximately 5%), or RET fusions (even less). Beyond TP53 status, Falk et al. also raise the possibility that rare XPO1 genomic alterations (mutation or amplification) could influence sensitivity to selinexor. Although such events appear uncommon in NSCLC, this remains an important consideration for future studies, particularly as resistance mechanisms to targeted therapies become increasingly actionable. Noted by Nagasaka et al., alterations affecting the selinexor binding site (including XPO1 C528S substitutions) have been described as a potential mechanism of resistance to selective inhibitors of nuclear export.

In summary, the thoughtful commentaries by Falk and Nagasaka reinforce the potential of XPO1 inhibition as part of the precision medicine toolkit for KRAS mutant NSCLC. We await further preclinical and clinical investigation in this promising area.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Lung Cancer Research. The article did not undergo external peer review.

Funding: This work was supported in part by the University of Texas Lung Specialized Program of Research Excellence (SPORE) (P50CA070907-21; to D.E.G.) and the UT Southwestern Dean’s Scholar in Clinical Research Program (to M.S.v.I.).

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-1-1493/coif). M.S.v.I. reports travel support from Kona Thoracic Oncology Meeting and pending US patent application (UTSD: 4434). D.E.G. reports research funding from Astra-Zeneca, BerGenBio, Karyopharm, and Novocure; stock ownership in Gilead; royalties from Oxford University Press; consulting/advisory board participation for Abbvie, Astra-Zeneca, Bayer, Catalyst Pharmaceuticals, and GSK; data and safety monitoring board participation for Daiichi-Sankyo, Summit Therapeutics, and Taiho Oncology; US Patents 11,747,345 and 12,498,831; US patent applications 17/045,482, 63/386,387, 63/382,972, and 63/382,257; and serving as Co-founder and Chief Medical Officer of OncoSeer Diagnostics, Inc. The authors have no other 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.

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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