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Endoplasmic Reticulum Stress and Disease / Pi3k/akt/mtor Signaling in Cancer · Journal article
Neoplasia · August 18, 2026
Early or partial results. Treat as a signal, not a conclusion.
This is a preclinical combination study demonstrating that omeprazole pretreatment followed by sotorasib and selinexor suppresses colony formation in sotorasib-resistant KRAS G12C NSCLC cell lines and inhibits tumor growth in a xenograft model. The work is mechanistic proof-of-concept showing XPO1 protein suppression with the three-drug regimen; it does not establish clinical safety, efficacy, or tolerability and warrants clinical exploration.
In vitro cell line study and mouse tumor xenograft model. KRAS G12C-mutant NSCLC cell lines, including H2030 which is resistant to both sotorasib and selinexor; H2030 cell-derived xenografts in mice. Intervention: Omeprazole pretreatment followed by sotorasib and selinexor combination.
Three-drug combination (omeprazole, sotorasib, selinexor) almost completely suppressed colony formation in four KRAS G12C cell lines (NCI-H358, NCI-H23, NCI-H2030, NCI-H358R) Selinexor plus omeprazole and sotorasib completely suppressed XPO1, AURKA, survivin, YAP1, and MRAS protein expression, whereas sotorasib alone did not suppress XPO1 In H2030 xenograft model, tumor growth was significantly inhibited by three-drug combination with no apparent toxic side-effects or weight loss observed
Toxicology assessed only by weight and clinical observation; no formal toxicity grading or pharmacokinetic data reported
This finding is preliminary and does not yet warrant clinical implementation. The three-drug combination concept warrants clinical exploration, but human studies are needed to establish safety, tolerability, and efficacy in KRAS G12C-mutant NSCLC patients.
Early-phase in vitro and xenograft study showing proof-of-concept for a three-drug combination in KRAS G12C NSCLC cells; mechanistic finding without human clinical data or toxicology beyond weight observation.
As stated by the source record.
Quoted from the source exactly as published.
This finding is preliminary and does not yet warrant clinical implementation. The three-drug combination concept warrants clinical exploration, but human studies are needed to establish safety, tolerability, and efficacy in KRAS G12C-mutant NSCLC patients.
Graded across the dimensions that decide whether you should act, each from what the source actually supports. There is no single score, and where a dimension was not assessed it says so.
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.
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