Abstract IA012: Targeting the oncogenic state of RAS: lessons from tri-complex inhibitors

Abstract RAS oncogenic driver mutations are among the most frequent genomic aberrations in human cancers, prevalent in pancreas (∼90%), colon (∼50%), and lung (∼30%) tumors. Small molecule inhibitors that selectively target the inactive, GDP-bound (OFF) state of KRAS G12C mutant proteins have demonstrated clinical efficacy as monotherapy in NSCLC and in combinations with anti-EGFR agents in CRC. However, there are no currently approved RAS-targeted therapy options for patients with non-G12C RAS mutant cancer. We have designed a series of orally bioavailable tri-complex inhibitors that selectively target the GTP-bound, active state of RAS (RAS(ON)), potentially mitigating some of the resistance mechanisms observed with inhibitors that preferentially bind to the OFF state. These include daraxonrasib (RMC-6236), a RAS(ON) multi-selective inhibitor that noncovalently inhibits the active, GTP-bound state of mutant and wild-type variants of all canonical RAS isoforms (KRAS, NRAS, and HRAS), and the mutant-selective inhibitors zoldonrasib (RMC-9805) that covalently engages RAS(ON) G12D, elironrasib (RMC-6291) that covalently engages RAS(ON) G12C, and RMC-5127 (our most recent clinical-stage agent) that noncovalently engages RAS(ON) G12V mutant proteins. These investigational agents demonstrate profound antitumor activity in preclinical models of RAS-addicted PDAC and NSCLC, which in the case of daraxonrasib, elironrasib, and zoldonrasib, has translated into encouraging (albeit early) antitumor activity with a manageable safety profile in patients with RAS mutant advanced PDAC and NSCLC. I will describe the mechanism of action of these RAS(ON) inhibitors and their activity in a variety of RAS-driven preclinical models that has supported their clinical development in RAS-dependent cancers, now moving into evaluation in earlier lines of therapy. Moreover, I will describe our emerging understanding of acquired resistance to RAS(ON) inhibitor monotherapy in both preclinical and clinical settings that is informing potential combination regimens for clinical evaluation, including RAS(ON) inhibitor doublets to address resistance mechanisms. Placing these agents in context of the overall RAS inhibitor landscape, I will discuss what lies ahead for RAS inhibitors including potential applications in cancers with unmet medical need, novel combinations, and the potential use of RAS inhibition for disease interception and prevention. Citation Format: Mallika Singh. Targeting the oncogenic state of RAS: lessons from tri-complex inhibitors [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RAS Oncogenesis and Therapeutics; 2026 Mar 5-8; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(5_Suppl_1):Abstract nr IA012.