Targeting adaptive EGFR feedback enhances the therapeutic efficacy of RMC-6236 in cholangiocarcinoma

Approximately 20% of cholangiocarcinomas harbor KRAS mutations, with codon 12 variants accounting for most of the cases. Among these, G12V is associated with a poor prognosis, whereas G12D is the most frequent subtype. RMC-6236, a novel RAS (ON) multi-selective inhibitor targeting multiple KRAS codon 12 mutations, has shown promise in early clinical studies in KRAS-mutant cholangiocarcinomas. We evaluated the therapeutic efficacy of the novel RAS (ON) inhibitor RMC-6236 as a monotherapy and in combination with gemcitabine and the anti-EGFR antibody cetuximab in KRAS-mutant cholangiocarcinoma (CCA) models. Antitumor activity and signaling alterations were assessed using in vitro cell-based assays, western blot analysis, and in vivo xenograft models. RMC-6236 potently inhibited cell proliferation in KRAS-mutant (G12D and G12V) cell lines at nanomolar concentrations (10–30 nM) and effectively suppressed pERK signaling. Notably, RMC-6236 treatment was accompanied by increased pEGFR expression, indicating adaptive EGFR feedback activation as a potential mechanism of resistance. In vitro, combination treatments significantly enhanced growth inhibition compared with monotherapy. In xenograft models, RMC-6236 treatment induced dose-dependent tumor regression, whereas combination with cetuximab or gemcitabine further enhanced the antitumor efficacy. EGFR-mediated feedback represents a targetable vulnerability in KRAS-mutant cholangiocarcinomas. Targeting EGFR signaling attenuates adaptive feedback reactivation induced by pan-RAS (ON) inhibition and supports the clinical development of combination strategies with EGFR blockade or cytotoxic chemotherapy.