Mechanisms of Resistance to KRASG12C-Targeted Therapy

KRAS mutations are among the most common drivers of human carcinogenesis, and are associated with poor prognosis and an aggressive disease course. With the advent of KRAS G12C inhibitors, the RAS protein is now targetable, with such inhibitors showing marked clinical responses across multiple tumor types. However, these responses are short-lived due to the development of resistance. Preclinical studies now suggest MAPK reactivation, stimulation of CDK4/6-dependent cell cycle transition, and immune defects as possible mechanisms of resistance. Devising strategies to overcome such resistance mechanisms, which are a barrier to long-term clinical response, remain an active area of research.