Bracing for the storm: emerging resistance mechanisms to KRAS inhibitors in pancreatic cancer and strategies to overcome them.

Oncogenic KRAS mutations are a defining feature of pancreatic ductal adenocarcinoma (PDAC), one of the most lethal solid malignancies, characterized by poor responsiveness to chemotherapy. Recent clinical successes of direct KRAS inhibitors in other cancer types have renewed interest in KRAS-directed therapy for PDAC. However, early clinical experience has revealed often short-lived responses, highlighting the rapid emergence of resistance and the need to understand the mechanisms limiting durable benefit. This review summarizes current knowledge on molecular resistance to RAS-directed inhibitors in PDAC, organized into five categories: intrinsic resistance, KRAS-dependent mechanisms, KRAS-independent bypass signaling, downstream pathway reactivation, and tumor microenvironment (TME)-mediated resistance. Evidence from PDAC models is integrated with insights from other KRAS-driven malignancies, particularly non-small cell lung cancer, where direct KRAS inhibition has been studied extensively. Collectively, resistance appears to arise from layered adaptive processes rather than single alterations, including secondary KRAS mutations, receptor tyrosine kinase-driven bypass signaling, reactivation of mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways, stromal-mediated protection, and reduced drug exposure. Notably, until recently, most evidence in PDAC has been indirect, while direct investigation of resistance mechanisms in KRAS-targeted settings has expanded rapidly only in recent years. Building on these advances, ongoing clinical trials increasingly explore rational combination strategies targeting upstream regulators, downstream effectors, and the TME. However, critical challenges persist, including patient selection, treatment sequencing, toxicity, and the lack of pharmacodynamic frameworks. Overcoming resistance will require mechanistically guided combinations, improved disease-specific models, and biomarker-driven adaptive strategies to ultimately achieve durable clinical benefits in PDAC.