Recent advances in mechanisms of KRAS<sup>G12C</sup> inhibitors anti-tumor resistance and relevant overcoming strategies

VernacularTitle:KRAS^G12C抑制剂抗肿瘤耐药机制及克服策略研究进展
Author: Ke-xin LIU ; Rui-lin WU ; Tao YUAN ; Kai-yue PU ; Qiao-jun HE ; Hong ZHU ; Bo YANG
Publication Type:Research Article
Keywords: KRAS; G12C mutation; oncogene; targeted therapy; rug resistance
From: Acta Pharmaceutica Sinica 2022;57(2):271-276
CountryChina
Language:Chinese
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 KRAS^G12C 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 KRAS^G12C 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 KRAS^G12C inhibitors, and discuss the mechanisms underlying KRAS^G12Cinhibitor resistance, so as to provide the clues for the combat of drug resistance.