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

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.