Abstract KRAS oncogenic driver mutations are among the most frequent genomic aberrations in human cancers, prevalent in pancreas, colon, and lung tumors. Small molecule inhibitors that selectively target the inactive, GDP-bound state of KRAS G12C mutant proteins have demonstrated clinical efficacy as monotherapy in NSCLC and in combinations 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 tri-complex inhibitors that selectively target the GTP-bound, active state of RAS (RAS (ON) ), thereby 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 GTP-bound state of mutant and wild-type variants of the canonical RAS isoforms (KRAS, NRAS, and HRAS), and the mutant-selective inhibitor zoldonrasib (RMC-9805) that covalently engages RAS (ON) G12D. These investigational agents demonstrate profound antitumor activity in preclinical models of RAS-addicted PDAC, which has translated into promising monotherapy clinical activity. We will describe the mechanism of action of these investigational agents and their activity in a variety of RAS-driven preclinical models supporting their clinical evaluation in RAS-addicted cancers. Moreover, we will describe our emerging understanding of acquired resistance to RAS (ON) inhibitor monotherapy that is informing potential combination regimens, including with RAS (ON) inhibitor doublets. Citation Format: Mallika Singh. Targeting the Oncogenic State of RAS in Pancreatic Cancer with Tri-Complex Inhibitors abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85 (18Suppl₃): Abstract nr IA02.
Mallika Singh (2025) studied this question.