Identification of Candidate Alterations Mediating KRASG12C Inhibitor Resistance in Advanced Colorectal and Pancreatic Cancers

Abstract Purpose: KRAS G12C inhibitors can treat KRASG12C-mutant advanced colorectal cancers and pancreatic ductal adenocarcinomas (PDAC), but alterations in Kirsten rat sarcoma (KRAS), EGFR, BRAF, MAP2K1, and other genes bypass KRAS inhibition and reduce therapy efficacy. Our study evaluates the genetic landscape of candidate primary resistance alterations relevant to KRAS targeting in KRASG12C-mutant colorectal cancer and PDAC. Experimental Design: We analyzed two cohorts (national database and Mayo) of patients with advanced colorectal cancer or PDAC tested with next-generation sequencing of ctDNA via Guardant360. Cohorts were divided into three groups: KRASG12C alone (KRASG12C without a resistance gene), KRASG12C with resistance (KRASG12C and ≥1 candidate resistance gene), and KRAS not detected. Candidate resistance mutations were inferred from the reported literature. Results: Among the national (13,603 colorectal cancer and 5,016 PDAC cases) and Mayo (741 colorectal cancer and 422 PDAC cases) cohorts, resistance alterations were identified in a considerable number of KRASG12C cases (46.5% of national colorectal cancer, 16.4% of national PDAC, 53.8% of Mayo colorectal cancer, and 36.4% of Mayo PDAC). The presence of resistance alterations was associated with a trend toward worse overall survival in KRASG12C colorectal cancer (P = 0.05). Conclusions: Putative resistance alterations are prevalent in PDAC and colorectal cancer and may limit monotherapy efficacy. Identifying these alterations has potential implications in optimal patient selection for targeted therapies and the development of combination therapy strategies to overcome primary resistance.