Journal Article Review Epublish
PubMed: 42729994 DOI: 10.20517/cdr.2026.52
Bracing for the storm: emerging resistance mechanisms to KRAS inhibitors in pancreatic cancer and strategies to overcome them.
Cancer Drug Resist 9:31
Authors: Marco Pagano Mariano, Enrica Sgarilli, Dirk Mijnlieff, Bonifiya Visuvasam, Andrea Blesio, Graziana Digiacomo, Andrea Cavazzoni, Manuela Ferracin, Elisa Giovannetti
Affiliations
- Department of Medical and Surgical Sciences, University of Bologna, Bologna 40126, Italy. Department of Medicine and Surgery, University of Parma, Parma 43126, Italy. Authors contributed equally.
- Department of Medicine and Surgery, University of Parma, Parma 43126, Italy. Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit, Amsterdam 1081 BT, the Netherlands. Authors contributed equally.
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit, Amsterdam 1081 BT, the Netherlands.
- Department of Medicine and Surgery, University of Parma, Parma 43126, Italy. Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit, Amsterdam 1081 BT, the Netherlands.
- Department of Medicine and Surgery, University of Parma, Parma 43126, Italy.
- Department of Medical and Surgical Sciences, University of Bologna, Bologna 40126, Italy.
- Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna 40126, Italy.
- Cancer Pharmacology Lab, Fondazione Pisana per la Scienza, San Giuliano 56017, Italy.
Abstract
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.
MeSH
Pancreatic Neoplasms, Autophagy, Neoplasms, Therapeutics, Mutation, Tumor Microenvironment