Issues

Allele-specific inhibitors of KRAS^G12C such as MRTX849 (adagrasib) and AMG 510 (sotorasib) have moved into clinical testing and elicit responses in a subset of patients, particularly those with non–small cell lung cancer (NSCLC). However, responses are not durable, necessitating the characterization of acquired resistance mechanisms to guide future combination treatment strategies and development of next-generation KRAS inhibitors. Tanaka, Lin, Li, and colleagues analyzed serial cell-free DNA from a patient with KRAS^G12C-mutant NSCLC who initially had a partial response but then developed resistance to adagrasib. Polyclonal resistance alterations converging upon reactivation of RAS/MAPK signaling were identified, including a secondary KRAS^Y96D mutation in the switch-II pocket where adagrasib and other inactive-state inhibitors bind that disrupts protein–drug interactions and confers resistance to these compounds in KRAS^G12C-mutant models. A functionally distinct tricomplex KRAS^G12C active-state inhibitor retained the ability to bind and inhibit KRAS^G12C/Y96D and could overcome resistance. For more information, see the article by Tanaka, Lin, Li, and colleagues on page 1913.