Abstract B068: FYN and other Src family kinases antagonize response to RAS inhibition in pancreatic ductal adenocarcinoma
Abstract
Oncogenic KRAS drives pancreatic ductal adenocarcinoma (PDAC), yet resistance to RAS antagonists limit benefits. To define therapeutic response and resistance mechanisms, we deployed two complementary preclinical PDAC models, including a degron-regulated KRASG12D-dependent transplantation model, and a Kras G12V-driven PDAC mouse model treated with the RAS(ON) multi-selective inhibitor, RMC-7977. KRASG12D degradation provoked RAS-dependent relapse, characterized by compensatory wild-type (WT) RAS upregulation, restored MAPK signaling and proliferation, and a shift towards hybrid cancer cell states. In contrast, RMC-7977 treatment triggered rapid RAS-independent resistance within 7 days, distinguished by suppressed MAPK yet restored proliferation with increased epithelial differentiation, and upregulation of Fyn. Mechanistically, this RAS-independent program converged on an Src-family kinase (SFK)-YAP axis. Antagonism of WT RAS or FYN attenuated resistance; and combining FYN/SFK antagonism with RMC-7977 prevented the uncoupling of MAPK signaling from cell proliferation in the respective Kras G12V PDAC model. Our findings identify distinct adaptive pathways orchestrating RAS-dependent versus RAS-independent resistance in PDAC and propose combination strategies for clinical evaluation to enhance KRAS-directed therapy durability. Hsiu-Chi Ting, Sun Y. Kim, Victoria Gaeth, Juliene Hinds, Astrid Deschenes, 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 and other Src family kinases antagonize response to RAS inhibition in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Conference on Pancreatic Cancer: New Frontiers in Biology and Therapeutic Development; 2026 Sep 25-28; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(18_Suppl_2):Abstract nr B068.