Abstract PR012: Encoding adaptive mechanisms of resistance to KRAS inhibition in pancreatic cancer

Abstract

Clinical outcomes for pancreatic ductal adenocarcinoma (PDAC) remain poor. Although ∼90% of PDAC tumors harbor oncogenic KRAS mutations and KRAS inhibitors (KRASi) have shown clinical promise, adaptive resistance limits response depth and durability. While EGFR-mediated RAS-MAPK pathway reactivation has been implicated in resistance, the underlying mechanisms remain poorly understood. We hypothesized that more complete and durable suppression of adaptive signaling pathways would enhance PDAC responses to KRAS-targeted therapies. Our objective was to define mechanisms of adaptive resistance and identify therapeutic strategies to overcome resistance and improve antitumor efficacy. Adaptive responses to KRAS-targeted therapies were investigated using temporal phosphoproteomics, drug combination screening, and clinical transcriptomic analyses. Patient-derived and cell-based PDAC models were used to evaluate therapeutic efficacy. We identified receptor tyrosine kinase-driven, cell-state-dependent reactivation of RAS-MAPK signaling following KRASi, whereas such reactivation was less prominent with RAS(ON) multi-selective inhibitors. EGFR mediated adaptive RAS-MAPK reactivation in epithelial PDAC models, whereas fibroblast growth factor receptor (FGFR) signaling promoted reactivation in mesenchymal models. To suppress adaptive MAPK pathway reactivation, mutant-selective KRASi were combined with RAS(ON) multi-selective inhibitors targeting both wild-type and mutant RAS. This strategy produced more consistent antitumor responses across PDAC models, regardless of cell state, than KRAS/EGFR co-inhibition. Across 10 PDAC models, phosphoproteomic analyses also identified Src family kinases (SFKs) as a robustly and consistently upregulated signaling node following multiple KRAS-targeting modalities. Mechanistically, SFK inhibition interfered YAP phosphorylations associated with YAP nuclear transcription, implicating SFK-YAP signaling in adaptive resistance. SFK inhibitors significantly enhanced the antitumor activity of KRAS-targeted therapies in vitro and in vivo, including models refractory to KRAS inhibition. Adaptive resistance to KRAS-targeted therapy in PDAC involves both cell-state-specific and conserved signaling mechanisms. EGFR and FGFR drive cell-specific RAS-MAPK reactivation following mutant-selective KRAS inhibition, whereas SFK activation represents a broadly conserved adaptive response across PDAC models and KRAS-targeting modalities. Combining KRASi with RAS(ON) multi-selective inhibitors or combining RAS(ON) multi-selective inhibitors with SFK inhibitors enhanced antitumor efficacy and suppressed adaptive signaling. This study defines adaptive resistance mechanisms to KRAS-targeted therapy in PDAC, revealing both cell-state-dependent RTK rewiring and a conserved SFK adaptive signaling axis. These findings provide a mechanistic rationale for either KRAS/pan-RAS or pan-RAS/SFK co-inhibition as strategies to improve responses to KRAS-targeted therapies in PDAC. Qingxiang Lin, Bokai Song, Conrad Sander, Candace Lei-Dadey, Alvin A. Morales-Giron, Elijiah Warren. Kushner, Do Hun. Kim, David T. Ting, Kristen M. Naegle, Forest M. White, Ryan B. Corcoran. Encoding adaptive mechanisms of resistance to KRAS inhibition in pancreatic cancer [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 PR012.