Targeting KRAS in Colorectal Cancer

Purpose of Review Mutations in kirsten rat sarcoma viral oncogene homolog (KRAS) are the most frequently observed genomic alterations in human cancers. No KRAS targeting therapy has been approved despite more than three decades of efforts. Encouraging progress has been made in targeting KRAS G12C with KRAS G12C specific covalent inhibitors in the past few years. Herein, we review the recent breakthroughs in KRAS targeting. Recent Findings KRAS G12C mutation was found in 14% of non-small cell lung cancer (NSCLC) and 3% of colorectal cancer. Recently, highly potent KRAS G12C specific inhibitors have been developed and demonstrated potent activity in preclinical models. Early results from phase 1 clinical trials with sotorasib and MRTX849 show promising antitumor activity in NSCLC, colorectal cancer and other solid tumors harboring KRAS G12C mutation. Summary For the first time, the preclinical success of targeting KRAS has translated into clinical benefits, which holds the potential of transforming clinical management of KRAS mutated solid tumors. Additional efforts are needed to identify biomarkers that predict response to KRAS inhibition in patients with KRAS G12C as well as to develop strategies to overcome resistance.