Abstract B004: EMT-associated integrin signaling drives resistance to RAS-GTP inhibition in pancreatic cancer

Abstract Targeting oncogenic RAS signaling has the potential to be effective for many RAS-addicted cancers, including pancreatic ductal adenocarcinoma (PDAC). However, the clinical efficacy of RAS-targeted therapies is frequently limited by innate or acquired resistance. While non-genetic alterations such as epithelial-to-mesenchymal transition (EMT) have been implicated in resistance, the precise mechanisms by which these adaptations circumvent RAS blockade remain poorly understood. Here, we define EMT-associated integrin signaling as a mediator of resistance to the RAS(ON) multi-selective inhibitor RMC-7977 in preclinical models of PDAC. Transcriptomic profiling of patient-derived PDAC organoids identified a robust correlation between RAS inhibitor resistance and expression of integrin and extracellular matrix (ECM)-associated gene signatures. We demonstrate that ECM attachment mediates RAS inhibitor resistance, implicating cell-ECM interactions as functionally involved in RAS independence. Quantitative phosphoproteomics revealed selective activation of Rho and Rac effector signaling kinases after RAS inhibition in mesenchymal resistant models. We utilized genetic and pharmacological approaches to establish Rho/Rac signaling as both necessary and sufficient for resistance in vitro. Critically, inhibition of integrin signaling components, including integrins, FAK, and PAK, restored sensitivity to RMC-7977 in vitro. Collectively, our preclinical results highlight integrin-mediated signaling as a key driver of EMT-associated RAS independence and implicate the potential of targeting this axis to overcome resistance to RAS inhibition in PDAC. Citation Format: Joshua H. Choe, Julien Dilly, Brendan Parent, Laleh Abbassi, Dennis Gong, Connor Hennessey, Nicole Sindoni, Fan Yi Kong, Kyle Evans, Jaclyn Varga-Wiles, Junning Wang, Baiqi Jiang, Jonathan DeLiberty, Dan Gui, Seema Chugh, Micaela Morgado, Jennifer A. Chan, William L. Hwang, Jonathan A. Nowak, Channing J. Der, Brian M. Wolpin, Clint A. Stalnecker, Joseph D. Mancias, Lewis C. Cantley, Andrew J. Aguirre. EMT-associated integrin signaling drives resistance to RAS-GTP inhibition in pancreatic cancer [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(18_Suppl_3):Abstract nr B004.