WCLC 2025 - Posters & ePosters-P2.02.39 Fulzerasib, a KRAS-G12C Inhibitor, Has Synergistic Antitumor Effect With Omeprazole Pretreatment in KRAS G12C NSCLC

P2.02.39 Fulzerasib, a KRAS-G12C Inhibitor, Has Synergistic Antitumor Effect With Omeprazole Pretreatment in KRAS G12C NSCLC

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This study investigates the synergistic antitumor effect of fulzerasib, a KRAS-G12C inhibitor, combined with omeprazole pretreatment in KRAS G12C-mutant non-small cell lung cancer (NSCLC). KRAS G12C inhibitors currently show limited efficacy and face resistance issues. Fulzerasib, a novel KRAS G12C inhibitor, demonstrates promising outcomes, including an objective response rate (ORR) of 49.1% and median progression-free survival (mPFS) of 9.7 months.<br /><br />The research aims to enhance fulzerasib efficacy by using omeprazole pretreatment to modulate multiple cancer signaling pathways. Dose-dependent viability assays show that omeprazole pretreatment significantly potentiates fulzerasib’s cytotoxic effect on NSCLC cells. Computational models confirm a synergistic interaction between the drugs, indicated by increased synergy zones in dose-matrix heatmaps.<br /><br />Western blot analysis reveals that the combination suppresses several key signaling pathways involved in tumor growth and survival. Specifically, the MRAS-PP1c-SHOC2 complex, phosphorylated Met (pMet), AKT (pAKT), and EphA2 (pEphA2) levels are downregulated more effectively with omeprazole pretreatment plus fulzerasib than with fulzerasib alone. This multi-pathway suppression likely underlies the enhanced antitumor activity.<br /><br />Additionally, omeprazole pretreatment improves fulzerasib's ability to inhibit colony formation in KRAS G12C-mutant NSCLC cells, indicating stronger long-term growth inhibition.<br /><br />In conclusion, omeprazole pretreatment synergistically enhances fulzerasib's efficacy through multi-pathway suppression, suggesting potential clinical benefits. The study proposes that (pre)treatment with omeprazole could improve fulzerasib therapy outcomes and delay the onset of resistance in KRAS G12C NSCLC patients. Future work includes in vivo validation and deeper mechanistic exploration to support clinical translation of this combination therapy.

Asset Subtitle

Mengxin Zhou

Meta Tag

Speaker Mengxin Zhou

Topic Tumor Biology – Preclinical Biology

Keywords

fulzerasib

KRAS G12C inhibitor

omeprazole pretreatment

non-small cell lung cancer

synergistic antitumor effect

multi-pathway suppression

MRAS-PP1c-SHOC2 complex

phosphorylated Met

AKT phosphorylation

colony formation inhibition