The gRASs Is Greener: Potential New Therapies in Lung Cancer with Acquired Resistance to KRASG12C Inhibitors

Summary:

Inhibitors of KRAS^G12C that bind the target in its inactive conformation and lock it in off-mode have shown early signs of clinical activity in patients with KRAS^G12C-mutant lung cancer, but responses tend to be short-lived and invariably prelude the development of acquired resistance through largely unexplored mechanisms. A new study describes the emergence of RAS–MAPK heterogeneous subclonal alterations in a patient relapsed on a KRAS^G12C inactive-state inhibitor and identifies a novel KRAS^Y96D-resistant variant that is druggable by a next-generation compound capable of associating with KRAS^G12C in its active configuration.