Abstract Oncogenic KRAS is the primary driver of pancreatic ductal adenocarcinoma (PDAC) and a critical therapeutic target. While both mutant-selective RAS inhibitors and RAS (ON) multi-selective inhibitors achieve initial tumor control, monotherapy resistance ultimately emerges and constrains clinical benefit. To define resistance trajectories and therapeutic opportunities for these respective targeted approaches, we leveraged two complementary preclinical systems, the selective degradation via the auxin-inducible degron 2 (AID2) system of oncogenic KRASG12D in orthotopically transplanted PDAC (TAK) model and the pharmacological inhibition of wild-type and mutant RAS by the tool RAS (ON) multi-selective inhibitor RMC-7977 in a KRASG12V-driven pancreatic cancer mouse model. Mutant-selective KRASG12D degradation provoked a RAS-dependent mode of relapse, characterized by compensatory upregulation of WT RAS proteins, the restoration of both MAPK signaling and tumor cell proliferation, and a decrease in mesenchymal cells and a shift towards hybrid cancer cell states. Conversely, inhibition of mutant and WT RAS (ON) by RMC-7977 treatment triggered rapid RAS-independent resistance within 7 days, distinguished by the persistent suppression of MAPK in the setting of restored proliferation and correlated with increased epithelial differentiation, and upregulation of Fyn. Antagonists of wild-type RAS or FYN/SFK attenuated resistance to RAS inhibition in the respective PDAC models; notably, combining FYN antagonism with RMC-7977 prevented the uncoupling of MAPK signaling from cell proliferation in the KRASG12V-driven pancreatic cancer mouse model. These preclinical findings demonstrate that distinct adaptive pathways orchestrate tumor rewiring and underlie RAS-dependent and RAS-independent resistance in PDAC and propose combination strategies for clinical evaluation to enhance the durability of KRAS-directed therapies. Citation Format: Hsiu-Chi Ting, Sun Y. Kim, Victoria Gaeth, Juliene Hinds, Astrid Deschênes, Amber N. Habowski, Peyton Smith, Heesang Yoo, Fatim Kouassi, Amanda Jensen, Julia Forte, Steven Portillo, Jonathan Kastan, Nicole M. Sodir, Youngkyu Park, Daniel A. King, Christopher R. Vakoc, Mallika Singh, David A. Tuveson. FYN antagonizes response to RAS inhibition in pancreatic ductal adenocarcinoma abstract. In: Proceedings of the AACR Special Conference in Cancer Research: RAS Oncogenesis and Therapeutics; 2026 Mar 5-8; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (5Suppl₁): Abstract nr B036.
Ting et al. (Thu,) studied this question.