Anticancer effects of an XPO1 inhibitor (selinexor) with sotorasib following omeprazole preconditioning in KRAS G12C-mutant non-small cell lung cancer cells in vitro and in a mouse tumor xenograft
TL;DR
In the H2030 xenograft model, tumor growth was significantly inhibited by treatment with the three-drug combination of omeprazole, sotorasib, and selinexor, with no apparent toxic side-effects or weight loss observed.
Abstract
Background KRAS G12C-mutant advanced non-small cell lung cancer (NSCLC) is currently treated with KRAS G12C covalent inhibitors, such as sotorasib, or RAS (ON) G12-selective inhibitors; however, response rates and progression-free survival remain limited, with recurrence occurring in most patients. Although mechanisms of resistance in KRAS G12C cell lines are multifarious, they have been attributed to EGFR activation and Aurora kinase A (AURKA) signaling via Ras-related nuclear protein (Ran). Ran-GTP cooperates with Exportin-1 (XPO1), which has been identified as essential in KRAS-mutant NSCLC cells. Methods KRAS G12C NSCLC cell lines, including H2030, which is resistant to sotorasib (KRAS G12C inhibitor) and selinexor (XPO1 inhibitor), were treated with sotorasib plus selinexor following pretreatment with omeprazole (a V-ATPase proton pump inhibitor) to assess effects on cell viability and protein expression. An in vivo study was also conducted using a KRAS G12C H2030 cell-derived tumor xenograft model. Results The combination of omeprazole with sotorasib and selinexor almost completely suppressed colony formation in the KRAS G12C-mutant cell lines tested (NCI-H358, NCI-H23, NCI-H2030, and NCI-H358R). While sotorasib did not influence XPO1 protein expression in any of the cell lines, the combination of selinexor, omeprazole and sotorasib completely suppressed XPO1 expression, as well as AURKA, survivin, YAP1, MRAS, and other key proteins. In the H2030 xenograft model, tumor growth was significantly inhibited by treatment with the three-drug combination of omeprazole, sotorasib, and selinexor, with no apparent toxic side-effects or weight loss observed. Conclusions XPO1 protein suppression is not achieved with sotorasib alone in KRAS G12C NSCLC cells. Notably, the combination of sotorasib, selinexor, and omeprazole abolishes the expression of XPO1, AURKA, YAP, and MRAS. The feasibility of therapy with XPO1 inhibition plus KRAS inhibitors warrants clinical exploration.