Background

KRAS is mutationally activated in >90% pancreatic ductal adenocarcinoma (PDAC), ~50% colorectal cancer (CRC), and ~30% NSCLC. KRAS mutations G12C, G12D and G12V are the most prevalent oncogenic drivers of cancers.

Only recently have inhibitors of KRAS G12C mutant been approved for clinical use: Sotorasib was approved by FDA in 2021, while Adagrasib was approved in 2022. In addition, MRTX1133, a potent KRAS G12D inhibitor, is in clinical trials for KRAS G12D-driven cancer. However, drug resistance has quickly developed during clinical application of Sotorasib and Adagrasib. Emergence of secondary mutations, such as KRAS G12C+Y96D, and activating mutations other than G12C, such as G12D, G12V, is one key mechanism responsible for the development of drug resistance to KRAS G12C