Abstract B084: Overcoming drug resistance of ‘tri-complex’ pan-RAS inhibitors: Inhibition of mTOR signaling

Abstract

Abstract Background: RAS mutations occur in ~20% of all cancers that drive tumor progression, and therapy targeting most predominant RAS mutations remains unavailable. Mutant-selective RAS inhibitors (RASi), such as FDA-approved KRAS G12C inhibitors, have demonstrated initial clinical responses but drug resistance frequently emerges that minimize the drug efficacy, mechanistically mediated by RAS signaling reactivation. Methods and Results: To address this challenge, we characterized a class of novel pan-RASi that universally inhibit all RAS mutations, which forms a ‘tri-complex’ with the chaperone protein (cyclophilin A) that specifically binds to RAS, including wild-type RAS (KRAS, NRAS, HRAS). Mutant-selective RASi induced RAS signaling rebound intensively, whereas pan-RASi enabling to inhibit wild-type RAS minimized this rebound, which was surmountable in a concentration-dependent manner. Importantly, pan-RASi abrogated cell viability in patient-derived KRAS-mutant cancer organoids rather than in normal patient-derived wild-type RAS organoids, implicating drug selectivity and manageable toxicity. Interestingly, intrinsic resistance to pan-RASi was rare in RAS-mutant cancer cell screening but was observed only in a handful of pancreatic and lung cancer cell lines. Our time-resolved signaling analyses of pan-RASi treatment showed the re-activation of mTOR signaling and a contrast correlation that mTOR signaling decreased in sensitive lines but remained in resistant lines, underscoring the critical contribution of mTOR pathways to RASi resistance. Mechanistically, we further identified mTOR signaling that drives intrinsic resistance to pan-RASi, and combined pan-RASi with mTOR inhibitors (mTORi) suppressed mTOR signaling in resistant lines, thereby improving efficacy. Conclusion: Pan-RASi hold promise in treating RAS-mutant cancer clinically and a combination of pan-RASi with mTORi can improve drug efficacy. Citation Format: Qingxiang (Nick) Lin. Overcoming drug resistance of ‘tri-complex’ pan-RAS inhibitors: Inhibition of mTOR signaling [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B084.