XPO1 inhibition selectively targets KRAS-mutant NSCLC cells by suppressing NFκB signaling.
Major finding: XPO1 inhibition selectively targets KRAS-mutant NSCLC cells by suppressing NFκB signaling.
Mechanism: Targeting XPO1 promotes accumulation of IκBα to inhibit NFκB signaling and reduce cell survival.
Impact: XPO1 inhibitors may be beneficial in treating patients with KRAS-mutant NSCLC.
Identifying bona fide synthetic lethal targets has proven challenging in KRAS-mutant cancers, potentially due to their phenotypic diversity. To enrich for true vulnerabilities in KRAS-mutant non–small cell lung cancer (NSCLC) cell lines, Kim and colleagues first analyzed transcriptomic variation across 106 human NSCLC cell lines to identify KRAS-independent background phenotypes and then performed a whole-genome siRNA toxicity screen in 12 NSCLC cell lines that were representative of the observed phenotypes. In total, 7,755 candidate siRNA pools reduced the viability of at least one KRAS-mutant cell line, and gene set enrichment analysis revealed 10 gene sets that were enriched in KRAS-mutant cells. Multiple nuclear transport machinery genes were common to all 10 gene sets, including the selective nuclear export receptor XPO1, which can be targeted with the clinically available inhibitor KPT-330 (also known as selinexor). Consistent with these findings, KRAS-mutant cell lines were more sensitive to XPO1 inhibition than wild-type cells, and XPO1 inhibition with KPT-330 specifically suppressed the growth of KRAS-mutant NSCLC xenografts, patient-derived xenografts, and genetically engineered mouse tumors. NFκB target genes were differentially expressed in cells sensitive to XPO1 inhibition compared with resistant cells, and treatment of sensitive cell lines with XPO1 inhibitors induced accumulation of the NFκB negative regulator IκBα, resulting in reduced NFκB activity. Depletion of IκBα conferred resistance to XPO1 inhibition, further indicating that suppression of NFκB signaling underlies the sensitivity of KRAS-mutant cells to XPO1 inhibition. Two KRAS-mutant NSCLC cell lines insensitive to XPO1 inhibition were found to harbor mutations in FSTL5, which is mutated in 10% of NSCLCs. FSTL5 mutations activated the YAP1 pathway to circumvent XPO1 dependence, but inhibition of YAP1 in FSTL5-mutant cells restored XPO1 inhibitor sensitivity. These findings suggest that XPO1 may be therapeutically targeted in KRAS-mutant NSCLC and provide insight into potential mechanisms of intrinsic XPO1 inhibitor resistance that may further help guide patient selection and treatment.