Covalent inhibitor targets KRas(G12C): A new paradigm for drugging the undruggable and challenges ahead

KRAS is one of the most commonly mutated oncogenes in cancers and therapeutics directly targeting the KRas have been challenging. Among the different known mutants, KRas(G12C) has been proved to be successfully targeted recently. Several covalent inhibitors selectively targeting KRas(G12C) have shown promising efficacy against cancers harboring KRAS(G12C) mutation in clinical trials and AMG510 (sotorasib) has been approved for the treatment of KRAS(G12C)-mutated locally advanced or metastatic non-small cell lung cancer. However, the overall responsive rate of KRas(G12C) inhibitors was around 50% in patients with non-small cell lung cancer and the efficacy in patients with colorectal cancer or appendiceal cancer appears to be less desirable. It is of great importance to discover biomarkers to distinguish patients who are likely benefitted. Moreover, adaptive resistance would occur inevitably with the persistent administration like other molecularly targeted therapies. Several combinatorial regimens have been studied in an effort to potentiate the efficacy of KRas(G12C) inhibitors in preclinical settings. This review summarized the recent progress of covalent KRas(G12C) inhibitors with a focus on identifying biomarkers to predict or monitor the efficacy and proposing rational drug combinations based on elucidation of the mechanisms of drug resistance.