Recent advances in mechanisms of KRASG12C inhibitors anti-tumor resistance and relevant overcoming strategies / 药学学报

ABSTRACT

KRAS is one of the most frequently mutated human oncogenes. In spite of mounting efforts on the development of direct or indirect inhibition targeting KRAS, little has been achieved because of insurmountable difficulties, titling KRAS "undruggable". Recently, subtype-specific inhibitors have shown great hope. Some KRASG12C inhibitors have entered clinical trials, including adagrasib and sotorasib, and have shown preliminary clinical effectiveness. Experiences from the inhibitors targeting the downstream factors of RAS pathways show that the anticancer activity of these drugs will be limited due to the development of drug resistance. Preclinical studies of KRASG12C inhibitors have revealed that the application of these agents might be hampered by the drug resistance issue. The current review aims to describe the current status of KRASG12C inhibitors, and discuss the mechanisms underlying KRASG12C inhibitor resistance, so as to provide the clues for the combat of drug resistance.