Targeting KRASG12C Mutation: Development of effective strategies to overcome drug resistance and limited efficacy

The KRAS^G12C mutation causes the KRAS protein to remain in a constantly activated state, thereby promoting cell proliferation and cancer progression. As researchers have transitioned the KRAS^G12C mutation from being “undruggable" to “druggable", the development of KRAS^G12C inhibitors has reached a peak. However, some KRAS^G12C inhibitors have shown resistance in preclinical studies and clinical trials, resulting in poor clinical outcomes and limiting their application. This review summarizes emerging strategies to overcome resistance, including optimization strategies for KRAS^G12C mutation site inhibitors (including covalent inhibitors and degraders), as well as potential therapeutic strategies involving combination therapies and multi-target inhibition targeting major resistance mechanisms. Additionally, it discusses the potential issues and challenges that may arise in the development of treatments for KRAS^G12C mutation resistance. It is hoped that this review can provide insightful perspectives to help overcome KRAS^G12C inhibitor resistance.