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 H&E staining and confirmed by 3-dimensional, cellular-resolution reconstruction of pancreata (CODA). Residual premalignant cells exhibited elevated cell death in the presence of RMC-7977 compared to control. Extended treatment with RMC-7977 (28 days) led to more profound elimination of PanIN lesions. This decreased neoplastic burden delayed tumor onset by a mean of 36.5 +/- 6 days and increased overall survival (OS) by 1.2-fold. Long-term interception with metronomic administration (1 week on/1 week off) of RMC-7977 in KPC mice resulted in near tripling of median tumor-free survival and OS, extending median survival to 376 +/- 106 days compared to 138 +/- 38 days in non-intercepted controls. Evaluation of escape tumors arising under long-term interception revealed aggressive tumors typical of the KPC model that retained some sensitivity to continued RAS inhibition. Notably, long-term cancer interception with RMC-7977 conferred a survival benefit of 25 weeks (p<0.0001) 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(8_Suppl):Abstract nr LB406.