KRAS in pancreatic cancer: from molecular biology to transformative therapeutics.
8 affiliations
- 1Division of Hematology and Oncology, Department of Medicine, Mayo Clinic Florida, Jacksonville, 32224, USA.
- 2Department of Medicine, Baptist Hospitals of Southeast Texas, Beaumont, USA.
- 3College of Biomedical Science, University of South Florida, Tampa, USA.
- 4Department of Medicine, National Institute of Diabetes and Endocrinology, Cairo, Egypt.
- 5Judy Genshaft Honors College, University of South Florida, Tampa, USA.
- 6Division of Hematology and Oncology, Department of Medicine, Mayo Clinic Rochester, Rochester, USA.
- 7Division of Hematology and Oncology, Department of Medicine, Mayo Clinic Arizona, Scottsdale, USA.
- 8Division of Hematology and Oncology, Department of Medicine, Mayo Clinic Florida, Jacksonville, 32224, USA. [email protected].
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a near-universally lethal malignancy, with KRAS mutations driving tumorigenesis in over 90% of cases. For decades considered undruggable, oncogenic KRAS has now been therapeutically engaged across multiple mutational subtypes, a revolution precipitated by allele-specific covalent inhibitors and accelerated by the emergence of RAS(ON) multi-selective inhibitors. The pivotal phase 3 RASolute 302 trial of daraxonrasib, a pan-RAS(ON) inhibitor, demonstrated nearly doubled median overall survival (13.2 versus 6.7 months; HR 0.40; P < 0.0001) over standard chemotherapy in previously treated metastatic PDAC. Concurrently, mutation-selective G12D inhibitors (zoldonrasib, VS-7375, INCB161734), G12D-targeted protein degraders (setidegrasib), G12C-selective RAS(ON) compounds (elironrasib), and next-generation MEK inhibitors (atebimetinib) are advancing through clinical evaluation. This review synthesizes the biological basis of KRAS-driven oncogenesis in the pancreas, the mutational landscape and its prognostic implications, the structural and mechanistic evolution of KRAS inhibitor classes, contemporary and emerging clinical data from recent trials, toxicity profiles and their management, and resistance mechanisms. The field stands at an inflection point: daraxonrasib now redefines second-line PDAC management, while first-line combination regimens with daraxonrasib plus chemotherapy have produced an ORR of 58% in early-phase single-arm data, a result now being tested in the randomized RASolute 303 trial. The challenge ahead lies in translating these results into durable remissions through rational combination therapy and in overcoming acquired resistance.
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BibTeX
@article{abdelhakeem2026kras,
title = {{KRAS in pancreatic cancer: from molecular biology to transformative therapeutics.}},
author = {Ahmed Abdelhakeem and Nency Ganatra and Khujasta Gul and Harshi Saxena and Nehal Mohammed and Anzer Ashraf and Jeremy C Jones and Rayan Carr and Tanios Bekaii-Saab and Mitesh Borad and Hani Babiker and Bassam Sonbol and Conor O'Donnell and Jason Starr and Umair Majeed},
journal = {Journal of hematology \& oncology},
year = {2026},
month = oct,
doi = {10.1186/s13045-026-01863-x},
url = {https://europepmc.org/article/MED/42963543},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - KRAS in pancreatic cancer: from molecular biology to transformative therapeutics.
AU - Ahmed Abdelhakeem
AU - Nency Ganatra
AU - Khujasta Gul
AU - Harshi Saxena
AU - Nehal Mohammed
AU - Anzer Ashraf
AU - Jeremy C Jones
AU - Rayan Carr
AU - Tanios Bekaii-Saab
AU - Mitesh Borad
AU - Hani Babiker
AU - Bassam Sonbol
AU - Conor O'Donnell
AU - Jason Starr
AU - Umair Majeed
PY - 2026
DA - 2026/10/30
JO - Journal of hematology & oncology
DO - 10.1186/s13045-026-01863-x
UR - https://europepmc.org/article/MED/42963543
AB - Pancreatic ductal adenocarcinoma (PDAC) is a near-universally lethal malignancy, with KRAS mutations driving tumorigenesis in over 90% of cases. For decades considered undruggable, oncogenic KRAS has now been therapeutically engaged across multiple mutational subtypes, a revolution precipitated by allele-specific covalent inhibitors and accelerated by the emergence of RAS(ON) multi-selective inhibitors. The pivotal phase 3 RASolute 302 trial of daraxonrasib, a pan-RAS(ON) inhibitor, demonstrated nearly doubled median overall survival (13.2 versus 6.7 months; HR 0.40; P < 0.0001) over standard chemotherapy in previously treated metastatic PDAC. Concurrently, mutation-selective G12D inhibitors (zoldonrasib, VS-7375, INCB161734), G12D-targeted protein degraders (setidegrasib), G12C-selective RAS(ON) compounds (elironrasib), and next-generation MEK inhibitors (atebimetinib) are advancing through clinical evaluation. This review synthesizes the biological basis of KRAS-driven oncogenesis in the pancreas, the mutational landscape and its prognostic implications, the structural and mechanistic evolution of KRAS inhibitor classes, contemporary and emerging clinical data from recent trials, toxicity profiles and their management, and resistance mechanisms. The field stands at an inflection point: daraxonrasib now redefines second-line PDAC management, while first-line combination regimens with daraxonrasib plus chemotherapy have produced an ORR of 58% in early-phase single-arm data, a result now being tested in the randomized RASolute 303 trial. The challenge ahead lies in translating these results into durable remissions through rational combination therapy and in overcoming acquired resistance.
SN - 1756-8722
ER -