KRASG12R-Mutant Pancreatic Cancer Features Limited ERK/MAPK Transcriptional Activity and a Distinctive Tumor Microenvironment
Year: 2026
Type: article
Abstract: Patients with pancreatic ductal adenocarcinoma (PDAC) harboring KRASG12R mutations have increased overall survival relative to patients with KRASG12D/V mutations. To investigate the mechanisms underlying this differential outcome, we developed a genetically engineered mouse model (GEMM) harboring KrasG12R and Trp53R172H mutations (KrasLSL-G12R/+;Trp53LSL-R172H/+;p48Cre-ERTM). Unlike KrasG12D models, KrasG12R GEMMs exhibited limited tumorigenesis, with only 10% developing pancreatic tumors after 1 year. Additionally, mice harboring whole-body expression of KrasG12R remained healthy for over 1 year, whereas KrasG12D mice developed rapid multifocal disease. Comparison of KRAS mutant-selective transcription and signaling in murine and human PDAC cell lines, GEMMs, and patient-derived xenograft (PDX) mouse models revealed that direct KRAS-mediated PI3K activation is necessary for robust tumor initiation in GEMMs. Unexpectedly, KRAS was not the primary driver of PI3K activity in human PDAC cell lines and PDX models, regardless of KRAS mutation. KRASG12R and KRASG12D activated a similar pancreas-specific transcriptional network, but KRASG12R promoted these pathways less robustly due to limited ERK/MAPK nuclear translocation. Finally, KRASG12R human pancreatic tumors had an altered tumor microenvironment (TME) with reduced collagen deposition and metastatic liver invasion. Together, this study demonstrated that KRASG12R is capable of driving tumorigenesis despite the reduced ERK/MAPK nuclear translocation and transcriptional output. Although human KRASG12D- and KRASG12R-mutant tumors display unexpected similarities in PI3K activity, the differential ERK/MAPK signaling activity and the extrinsic consequences on the TME provide support for using KRASG12R mutation status as a prognostic biomarker for therapeutic strategies. SIGNIFICANCE: KRASG12R-mutant pancreatic cancer is characterized by lower ERK/MAPK nuclear translocation and transcriptional output than KRASG12D-mutant tumors, offering a potential window for patients with KRASG12R mutations to derive additional benefit from neoadjuvant therapy. See related commentary by Tiriac and Engle, p. 1817 See related article by Burge et al., p. 1854 See related article by Kamgar et al., p. 2042.
Source: Cancer Research
Authors: Rachel A. Burge, Ozgun Le Roux, Olesja Popow, Victoria K. Spadafora, Christabelle Rajesh, Sara J. Adair, Lucas Bialousow, Cailey Murphy, Samaneh Saberi, Silvia G. Vaena, Margaret C. Taquey, Sarah Allen, Lu Han, Kristi L. Helke, Sudarshana Sharma, Michael C. Ostrowski, Denis C. Guttridge, Toros A. Dincman, Todd W. Bauer, David F. Kashatus, Thomas McFall, Kevin M. Haigis, Michael A. Hollingsworth, Christopher M. Counter, Channing J. Der, G. Aaron Hobbs
Institutions: Medical University of South Carolina, Duke Medical Center, Brigham and Women's Hospital, Harvard University, Dana-Farber Cancer Institute, University of Virginia, MUSC Hollings Cancer Center, University of Virginia Health System, Medical College of Wisconsin, Medical College of Wisconsin Cancer Center, Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, University of North Carolina at Chapel Hill, UNC Lineberger Comprehensive Cancer Center
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Funders: U.S. Department of Defense, American Cancer Society, Abney Foundation, Concern Foundation, Pancreatic Cancer Action Network, Bristol-Myers Squibb, Medical University of South Carolina, Mark Foundation For Cancer Research, Duke-NUS Medical School, Mirati Therapeutics, Cancer Research UK, National Institutes of Health, Hollings Cancer Center, Medical University of South Carolina, National Cancer Institute, National Institute of General Medical Sciences, Duke Cancer Institute
Awards: G1319661684, G1410469566, G2221353213, G2949882231, G297978257, Biological Activity of Ras Oncogenes, Defining RAS isoform- and mutation-specific roles in oncogenesis, G3594737752, Targeting undruggable RAS for cancer treatment, G4223979924, Washington University SPORE in Pancreatic Cancer, Redefining indications of EGFR inhibitors in cancers that harbor mutant RAS, Origin, diversification and function of pancreatic cancer associated fibroblasts, G6224975242, G6397191437, G64548576, G704522546, Identification of synthetic lethal interactors in pancreatic cancer, G8439975161, G8442482983, TARGETING KRAS-DYSREGULATED METABOLISM FOR NOVEL THERAPEUTIC APPROACHES, Genetic dissection of oncogenic RAS-driven tumor initiation in vivo, Selective Targeting of Pancreatic Cancer SPORE, The role of the macroenvironment in pancreatic cancer-induced cachexia, COBRE in Digestive and Liver Disease, Pancreatic Cancer Detection Consortium, University of Virginia Cancer Center Support Grant, Medical University of South Carolina - Cancer Center Support Grant, Cancer Center Support Grant (CCSG), G974618274
OpenAlex ID: W7124868639