Identification of candidate alterations mediatin KRAS-G12C inhibitor resistance in advanced colorectal and pancreatic cancers

KRAS^G12C inhibitors can treat KRAS^G12C-mutant advanced colorectal cancer (CRC) and advanced pancreatic ductal adenocarcinom (PDAC), but other alteration in KRAS, EGFR, BRAF, MAP2K1, and other genes bypass KRAS inhibition and reduce therapy efficacy. Analysis of two cohorts (national database and Mayo) of patients with advanced CRC or PDAC tested with next-generation sequencing of ctDNA found co-occurring resistance alterations in 46.5% and 53.8% of the two CRC cohorts and 16.4% and 36.4% of the two PDAC cohorts. The presence of resistance alterations was associated with a trend towards worse overall survival in KRAS^G12C colorectal cancer (p=0.05). The authors conclude that putative resistance alterations are prevalent in KRAS^G12C altered CRC and PDAC and may limit monotherapy efficacy.