Genetic alterations associated with KRAS(G12C) inhibitor resistance

Inactive state-selective KRAS(G12C) inhibitors demonstrate a 30-40% response rate and a ~6 month median progression-free survival in patients with lung cancer. The genetic basis for resistance to these first-in-class mutant GTPase inhibitors remains under investigation. Here we report that resistance to KRAS(G12C) inhibition was associated with hotspot mutations in KRAS(G12V or G13D), NRAS(Q61K or G13R), MRAS(Q71R) and/or BRAF(G596R). Our study suggests a heterogenous pattern of resistance with multiple subclonal events emerging with G12Ci-treatment.