Overcoming Resistance to Drugs Targeting KRAS^G12C Mutation

Activating KRAS mutations are present in 25% of human cancer. Although oncogenic Ras was deemed “undruggable” in the past, recent efforts led to the development of pharmacological inhibitors targeting the KRAS^G12C mutant, which have shown promise in early clinical trials. The development of allele-specific K-Ras^G12C inhibitors marked a new chapter in targeting oncogenic KRAS mutant in cancer. However, drug resistance against these new drugs will likely limit their efficacy in the clinic. Genome-wide approaches have been used to interrogate the mechanisms of resistance to K-Ras^G12C inhibitors, which would facilitate the development of therapeutics overcoming drug resistance. This article reviews the latest progress in resistance to K-Ras^G12C-targeted therapies and aims to provide insight in future research targeting drug resistance in cancer.