Abstract
RAS mutation is considered one of the most relevant oncogenic drivers in human cancers. Unfortunately, for more than three decades, RAS has been considered an undruggable target. Recently, the discovery of selective and potent KRAS(G12C) inhibitors represented a light at the end of the tunnel. Indeed, sotorasib and adagrasib proved clinical activity in patients with refractory metastatic colorectal cancer harboring KRAS(G12C) mutation; however, responses are lower than expected, suggesting the presence of intrinsic resistance. Consequently, novel combinatory strategies to disrupt the RAS signaling pathways are under clinical investigation. This review aims to discuss the current knowledge and novel routes of KRAS(G12C) inhibition in metastatic colorectal cancer.