Abstract PR008: EMT-associated focal adhesion signaling mediates resistance to RAS inhibition

Abstract

Direct inhibition of oncogenic RAS has emerged as a clinically active therapeutic strategy for RAS-addicted cancers, including pancreatic ductal adenocarcinoma (PDAC). However, resistance is likely to limit the durability of therapeutic response, motivating combination strategies that target adaptive survival mechanisms. To identify compounds capable of enhancing RAS inhibitor response across heterogeneous resistant states, we conducted a combination pharmacological screen pairing the RAS(ON) multi-selective tri-complex inhibitor RMC-7977 with a curated compound library across KRAS-mutant cancer cell lines spanning diverse tumor lineages, genetic backgrounds, and cell states. Focal adhesion signaling emerged as a targetable vulnerability associated with epithelial-to-mesenchymal transition (EMT). In preclinical PDAC models, innate and acquired resistance were further linked to extracellular matrix (ECM) and integrin interaction programs. Functionally, mesenchymal PDAC cells required ECM attachment to maintain both integrin-FAK-Rac signaling and RAS inhibitor resistance. Quantitative time-course phosphoproteomics identified Rho effector kinase signaling as the dominant adaptive response to RAS inhibition. CRISPR screening revealed heightened dependence on focal adhesion pathway components during RAS blockade. Targeted genetic and pharmacological perturbations of the integrin-FAK-Rac signaling axis enhanced RAS inhibitor response in vitro, and the combination of clinical-grade RAS(ON) inhibitors and FAK inhibition improved antitumor activity in vivo. Collectively, this study establishes attachment-dependent focal adhesion signaling as a targetable mediator of EMT-associated RAS inhibitor resistance and provides a comparative resource for prioritizing combination strategies across diverse KRAS-mutant cancer contexts.