Abstract LB406: Active RAS inhibition intercepts pancreas cancer in mice

Abstract Cancer interception is a clinical approach to eliminate pre-malignant lesions, distinct from approaches to treat invasive cancer, but effective strategies in pancreatic ductal adenocarcinoma (PDAC) remain to be identified. Conceptually, interception strategies should target precancerous lesions such as pancreatic intraepithelial neoplasia (PanINs) to prevent malignant transformation. Because PanINs overwhelmingly harbor oncogenic KRAS mutations as an inceptive genetic event, we utilized a mouse model of PDAC to evaluate the potential of RAS inhibition to intercept pancreas premalignancy. Short-term treatment (10 days) of PanIN-bearing, tumor-free KrasG12D Trp53R172H/+ Pdx1-Cre (KPC) mice with the RAS (ON) multi-selective inhibitor RMC-7977 reduced the prevalence of premalignant lesions, as assessed by H0. 0001) compared to the use of RMC-7977 at the time of cancer diagnosis in KPC mice. We conclude that targeted pharmacological cancer interception reduces premalignant PanIN lesions and substantially extends survival in preclinical models of PDAC, supporting clinical evaluation of RAS inhibitors for pancreatic cancer interception. Citation Format: Minh T. Than, Lucie Dequiedt, Rina Sor, Shreya Nair, Nune Markosyan, Emma E. Furth, Chenghua Yang, Courtney Ray-Fofana, Marie Menard, Elsa Quintana, A Cole Edwards, Connor J. Hennessey, Austin L. Good, Liz Quinones, Yunseo Hwang, Cynthia Clendenin, Ashley L. Kiemen, Robert H. Vonderheide, Ben Z. Stanger. Active RAS inhibition intercepts pancreas cancer in mice abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr LB406.