Molecular Subtyping and Genomic Profiling Expand Precision Medicine in KRAS Wild-Type Pancreatic Cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease with poor prognosis and limited treatment options. While the majority of PDAC cases harbor KRAS mutations, approximately 8%–10% are KRAS wild-type (KRAS-WT). These KRAS-WT tumors often contain actionable mutations and gene fusions, making them more suitable for precision therapies. Identifying these molecular alterations is crucial for improving outcomes in this subset of patients. This retrospective study involved 34 patients with KRAS-WT PDAC. Genomic profiling was performed using next-generation sequencing (NGS) and RNA sequencing to detect mutations and fusions. Comparative analysis was conducted with TCGA-PAAD data, and immune infiltration was assessed using bioinformatic deconvolution methods. Targetable alterations were identified in multiple pathways. Key mutations included ATM (18%), PIK3CA (15%), and ROS1 (15%), while actionable gene fusions such as CCDC6-RET and ETV6-NTRK3 were present in 10.3% of patients. The gene mutations associated with homologous recombination deficiency (HRD) are predicted to increase sensitivity to platinum-based chemotherapy (p = 0.047). Tumors with epigenetic regulatory genes mutations (e.g., ARID1A, KMT2C/D) exhibited enhanced immune cell infiltration, highlighting potential responsiveness to immune checkpoint inhibitors (ICIs). Kinase fusions (NTRK and RET) were linked to response to larotinib and RET-specific inhibitors, respectively. KRAS-WT PDAC contains actionable mutations and fusions, offering significant potential for targeted and immune-based therapies. Further clinical studies are needed to validate these therapeutic approaches.