Reference - Detail
| RRC ID | 90158 |
|---|---|
| Author | Yamazaki S, Hondo N, Yasukawa K, Kitazawa M, Nakamura S, Yamamoto Y, Miyazaki S, Tanaka H, Kuroiwa M, Ishizaka N, Shimizu T, Shimizu A, Soejima Y. |
| Title | Targeting adaptive EGFR feedback enhances the therapeutic efficacy of RMC-6236 in cholangiocarcinoma. |
| Journal | Exp Hematol Oncol |
| Abstract |
BACKGROUND: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. METHODS: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. RESULTS: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. CONCLUSION: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. |
| Volume | 15(1) |
| Published | 2026-10-3 |
| DOI | 10.1186/s40164-026-00835-8 |
| PII | 10.1186/s40164-026-00835-8 |
| PMID | 42829436 |
| PMC | PMC13633637 |
| Resource | |
| Human and Animal Cells | RBE(RCB1292) |