Differential Response and Resistance to KRAS‐Targeted Therapy

ABSTRACT KRAS is the most frequently mutated oncogene. In epithelial malignancies such as lung, colorectal, and pancreatic tumors, KRAS is mutated in 25 to above 90% cases. KRAS was considered undruggable for over three decades until the recent development of covalent inhibitors targeting the KRAS G12C mutant. The recent approval of the KRAS G12C inhibitors sotorasib and adagrasib has ushered in a new era of KRAS‐targeted therapy. Despite this success, a major challenge in KRAS‐targeted therapy is intrinsic and acquired resistance to KRAS inhibitors. Clinical studies have shown that many patients with KRAS G12C cancers did not respond to sotorasib and adagrasib. Colorectal cancer, in particular, has a markedly lower response rate to KRAS G12C inhibitors compared to non‐small cell lung cancer. Furthermore, the therapeutic response to KRAS G12C inhibition was short‐lived, with quick emergence of acquired resistance. In this review, we summarize several major themes that have emerged from recent clinical and preclinical studies on the mechanisms of intrinsic and acquired resistance to KRAS‐targeted therapy in colorectal, lung, and pancreatic cancers. We also discuss various combination strategies for targeting these mechanisms to overcome resistance to KRAS inhibitors.