KRASG12R-Mutant Pancreatic Cancer Features Limited ERK/MAPK Transcriptional Activity and a Distinctive Tumor Microenvironment.

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 p53R172H mutations (KrasLSL-G12R/+;Trp53LSL-R172H/+;p48Cre-ERTM). Unlike KRASG12D models, KRASG12R-GEMMs exhibited limited tumorigenesis, with only 10% developing pancreatic tumors after one year. Additionally, mice harboring whole-body expression of KRASG12R remained healthy for over one 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 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 patient-derived xenograft 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.

Duke Scholars

Author Christopher M. Counter Pharmacology & Cancer Biology