Resistance looms for KRAS G12C inhibitors and rational tackling strategies.

KRAS mutations are one of the most frequent activating alterations in carcinoma. Recent efforts have witnessed a revolutionary strategy for KRAS G12C inhibitors with exhibiting conspicuous clinical responses across multiple tumor types, providing new impetus for renewed drug development and culminating in sotorasib with approximately 6-month median progression-free survival in KRAS G12C-driven lung cancer. However, diverse genomic and histological mechanisms conferring resistance to KRAS G12C inhibitors may limit their clinical efficacy. Herein, we first briefly discuss the recent resistance looms for KRAS G12C inhibitors, focusing on their clinical trials. We then comprehensively interrogate and underscore our current understanding of resistance mechanisms and the necessity of incorporating genomic analyses into the clinical investigation to further decipher resistance mechanisms. Finally, we highlight the future role of novel treatment strategies especially rational identification of targeted combinatorial approaches in tackling drug resistance, and propose our views on including the application of robust biomarkers to precisely guide combination medication regimens.