Mutation in KRAS protooncogene represents one of the most common genetic alterations in NSCLC and has posed a great therapeutic challenge over the past ~ 40 years since its discovery. However, the pioneer work from Shokat’s lab in 2013 has led to a recent wave of direct KRAS inhibitors that utilize the switch II pocket identified. Notably, two of the inhibitors have recently received US FDA approval for their use in the treatment of KRAS mutant NSCLC. Despite this success, there remains the challenge of combating the resistance that cell lines, xenografts, and patients have exhibited while treated with KRAS inhibitors. This review discusses the varying mechanisms of resistance that limit long-lasting effective treatment of those direct inhibitors and highlights several novel therapeutic approaches including a new class of KRAS (ON) inhibitors, combinational therapies across the same and different pathways, and combination with immunotherapy/chemotherapy as possible solutions to the pressing question of adaptive resistance.
© 2023. The Author(s).