Abstract PR012: Encoding adaptive mechanisms of resistance to KRAS inhibition in pancreatic cancer
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. CorcoranAbstract
Background:
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.
Hypothesis and Objective:
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.
Methods:
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.
Results:
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.
Conclusions:
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.
Significance:
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.
Citation Format:
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.