Abstract 5518: Targeting FAK by Ifebemtinib synergizes with Pan RAS inhibitors in treating RAS mutant cancers

Pan-RAS inhibitors have been developed for the treatment of RAS-mutant cancers. Despite the challenges in achieving clinical benefits, targeting Pan-RAS represents a novel strategy for treating these previously considered untargetable malignancies. Previous studies have demonstrated that targeting FAK enhances the therapeutic efficacy of KRAS G12C inhibition in clinical settings, as hyperactivated FAK signaling is a major mechanism of acquired resistance following KRAS G12C inhibition. In the present study, we observed that Pan-RAS inhibitors can induce acquired hyperactivity of FAK, potentially rendering cancer cells resistant to Pan-RAS inhibition. Co-administration of a clinical-stage FAK inhibitor, Ifebemtinib (also known as Ifebe, IN10018), with RMC6236, a Pan-RAS inhibitor, exhibited synergistic cytotoxic effects in multiple RAS-mutant cancer cell lines. Furthermore, we evaluated the dual regimen in KRAS-mutant and NRAS-mutant animal models, where the combination therapy demonstrated superior tumor growth inhibition compared to monotherapy. Our previous findings indicated that FAK inhibition in conjunction with KRAS G12C/G12D inhibition enhances the anti-cancer effects of PD-1 blockade. Here, we confirmed that the combination of Ifebe and RMC6236 also augments the anti-tumor efficacy of PD-1 antibody therapy, suggesting that this treatment enhancement is independent of the specific RAS mutation type. In summary, our study reveals that the combination of FAK inhibitor Ifebe with Pan-RAS inhibitor exhibits synergistic anti-cancer effects and further improves the outcomes of PD-1 blockade therapy. These preclinical results support the need for further clinical investigation. Citation Format: Baoyuan Zhang, Ran Pang, Jiaming Gao, Jingwen Cheng, Ping Zhang, Natasha Qin, Leo Liu, Zaiqi Wang. Targeting FAK by Ifebemtinib synergizes with Pan RAS inhibitors in treating RAS mutant cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5518.