Abstract
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.