WCLC 2025 - Posters & ePosters-P2.02.46 V-Atpase Inhibitors Enhance the Effect of Tepotinib (c-Met Inhibitor) or RMC-6236 (Pan-Ras(ON) Inhibitor) in KRAS-Mutant NSCLC

P2.02.46 V-Atpase Inhibitors Enhance the Effect of Tepotinib (c-Met Inhibitor) or RMC-6236 (Pan-Ras(ON) Inhibitor) in KRAS-Mutant NSCLC

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This study investigates the potential enhancement of anticancer effects in KRAS-mutant non-small cell lung cancer (NSCLC) by combining the V-ATPase inhibitor omeprazole with two targeted therapies: tepotinib (a c-Met inhibitor) and RMC-6236 (a pan-RAS inhibitor). NSCLC cell lines H358, H23, and A549 were pretreated with omeprazole before treatment with tepotinib or RMC-6236. Protein expression related to the RAS-MAPK and Wnt signaling pathways, critical for tumor growth and resistance mechanisms, was analyzed via Western blot after treatment.<br /><br />Key findings include that omeprazole pretreatment consistently increased the antitumor efficacy of both tepotinib and RMC-6236. The combination of omeprazole and tepotinib more effectively suppressed cancer-related signaling pathways compared to tepotinib alone. Notably, while RMC-6236 alone sometimes caused activation of early resistance pathways (similar to those triggered by FDA-approved KRAS G12C inhibitors such as sotorasib), co-treatment with omeprazole reversed these effects by reducing YAP1 activity, receptor tyrosine kinase activations, and MRAS expression. These molecular changes suggest that omeprazole can counteract adaptive resistance mechanisms, enhancing inhibitor efficacy.<br /><br />Synergistic effects of the drug combinations on cell viability were confirmed through MTT assays and computational synergy analysis. Results showed that omeprazole and RMC-6236 exerted a synergistic cytotoxic effect in the tested NSCLC cell lines. This preclinical evidence supports omeprazole as a promising adjuvant to improve responses to c-Met and pan-RAS inhibitors in KRAS-mutant NSCLC.<br /><br />In conclusion, omeprazole enhances the anticancer impact of tepotinib and RMC-6236 by modulating key signaling pathways and overcoming early adaptive resistance mechanisms. These findings offer a rationale for further exploration of combined regimens involving proton pump inhibitors to potentiate targeted therapies in difficult-to-treat KRAS-driven lung cancers.

Asset Subtitle

Kevin València-Clua

Meta Tag

Speaker Kevin València-Clua

Topic Tumor Biology – Preclinical Biology

Keywords

KRAS-mutant NSCLC

omeprazole

V-ATPase inhibitor

tepotinib

c-Met inhibitor

RMC-6236

pan-RAS inhibitor

RAS-MAPK signaling

Wnt signaling

adaptive resistance mechanisms