Synergizing Against RAS: The Evolving Landscape of Targeted Combinations in Pancreatic Cancer
7 affiliations
- 1Division of General Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA
- 2Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA
- 3Department of Oncology, Mayo Clinic, Jacksonville, FL 32224, USA
- 4Department of Oncology, Mayo Clinic, Scottsdale, AZ 85259, USA
- 5Department of Radiology, Mayo Clinic, Rochester, MN 55905, USA
- 6Department of Immunology, Mayo Clinic, Jacksonville, FL 32224, USA
- 7Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA
Abstract
Pancreatic ductal adenocarcinoma (PDAC), the most common histological subtype of pancreatic cancer, remains one of the most lethal solid malignancies, with most patients presenting with advanced disease and limited therapeutic options. Activating KRAS mutations are present in over 90% of PDACs and drive tumor initiation, progression, metabolic reprogramming, and immune evasion, making KRAS a central therapeutic target. Advances in drug development have transformed RAS from a historically “undruggable” oncogene into a clinically actionable target through the development of mutation-selective inhibitors, pan-RAS inhibitors, targeted degraders, and RNA-based therapies. The 2026 approval of daraxonrasib by the FDA for metastatic pancreatic cancer marked the first regulatory approval of a RAS-targeted inhibitor in pancreatic ductal adenocarcinoma and validated RAS blockade as a clinically actionable therapeutic strategy. This review highlights emerging combination strategies designed to maximize the therapeutic potential of RAS inhibition in PDAC. Early clinical studies combining KRAS-targeted therapies with standard chemotherapy have demonstrated encouraging response rates and have led to multiple ongoing phase III trials. As the field moves toward precision oncology, biomarker-driven patient selection, circulating tumor DNA monitoring, and adaptive clinical trial designs will be essential for translating these advances into meaningful survival benefits. Collectively, rational combination strategies represent the next frontier in KRAS-directed therapy and hold the greatest promise for improving outcomes in PDAC.
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BibTeX
@article{ghosh2026synergizing,
title = {{Synergizing Against RAS: The Evolving Landscape of Targeted Combinations in Pancreatic Cancer}},
author = {Aditya K. Ghosh and Khalid A. Jazieh and Hao Xie and Marie A. Parish and Hani M. Babiker and Tanios S. Bekaii-Saab and Ajit H. Goenka and Keith L. Knutson and Akhilesh Pandey and Martin E. Fernandez-Zapico and Ryan M. Carr and Ben George},
journal = {Cancers},
year = {2026},
month = nov,
doi = {10.3390/cancers18213519},
url = {https://www.mdpi.com/2072-6694/18/21/3519},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Synergizing Against RAS: The Evolving Landscape of Targeted Combinations in Pancreatic Cancer
AU - Aditya K. Ghosh
AU - Khalid A. Jazieh
AU - Hao Xie
AU - Marie A. Parish
AU - Hani M. Babiker
AU - Tanios S. Bekaii-Saab
AU - Ajit H. Goenka
AU - Keith L. Knutson
AU - Akhilesh Pandey
AU - Martin E. Fernandez-Zapico
AU - Ryan M. Carr
AU - Ben George
PY - 2026
DA - 2026/11/02
JO - Cancers
DO - 10.3390/cancers18213519
UR - https://www.mdpi.com/2072-6694/18/21/3519
AB - Pancreatic ductal adenocarcinoma (PDAC), the most common histological subtype of pancreatic cancer, remains one of the most lethal solid malignancies, with most patients presenting with advanced disease and limited therapeutic options. Activating KRAS mutations are present in over 90% of PDACs and drive tumor initiation, progression, metabolic reprogramming, and immune evasion, making KRAS a central therapeutic target. Advances in drug development have transformed RAS from a historically “undruggable” oncogene into a clinically actionable target through the development of mutation-selective inhibitors, pan-RAS inhibitors, targeted degraders, and RNA-based therapies. The 2026 approval of daraxonrasib by the FDA for metastatic pancreatic cancer marked the first regulatory approval of a RAS-targeted inhibitor in pancreatic ductal adenocarcinoma and validated RAS blockade as a clinically actionable therapeutic strategy. This review highlights emerging combination strategies designed to maximize the therapeutic potential of RAS inhibition in PDAC. Early clinical studies combining KRAS-targeted therapies with standard chemotherapy have demonstrated encouraging response rates and have led to multiple ongoing phase III trials. As the field moves toward precision oncology, biomarker-driven patient selection, circulating tumor DNA monitoring, and adaptive clinical trial designs will be essential for translating these advances into meaningful survival benefits. Collectively, rational combination strategies represent the next frontier in KRAS-directed therapy and hold the greatest promise for improving outcomes in PDAC.
SN - 2072-6694
ER -