Genetic Resistance to KRASG12C Inhibitors in CRC and PDAC

KRAS^G12C inhibitors are commonly used to suppress disease progression in KRAS^G12C-mutant advanced colorectal cancers (CRC) and pancreatic ductal adenocarcinomas (PDAC), but these treatments can have reduced efficacy in patients with alterations in KRAS, EGFR, and other genes.

A recent study has examined the genetic landscape of resistance alterations linked to KRAS targeting in KRAS^G12C-mutant CRC and PDAC.

Two patient cohorts taken from a national database (13,603 colorectal cancer and 5,016 PDAC cases) and Mayo Clinic (741 colorectal cancer and 422 PDAC cases) were analyzed, comprised of patients with advanced CRC or PDAC who were tested with next-generation sequencing of circulating tumor DNA using Guardant360.

Patients were placed into one of three groups: KRAS^G12C alone (KRAS^G12C without a resistance gene), KRAS^G12C with resistance (KRAS^G12C and ≥1 candidate resistance gene), and KRAS not detected.

Resistance alterations were found in a significant number of KRAS^G12C cases (46.5% of national CRC, 16.4% of national PDAC, 53.8% of Mayo Clinic CRC, and 36.4% of Mayo Clinic patients with PDAC). Resistance alterations correlated with a trend in worse overall survival in patients with KRAS^G12C CRC (P=0.05).

Resistance alterations in patients with PDAC and CRC may limit monotherapy efficacy. Determining these alterations is key for optimal patient selection for targeted therapies and creating combination therapy strategies to overcome primary resistance.