This paper discusses the rapidly evolving landscape of RAS inhibitor therapies for cancer, highlighting the recent approval of two mutant-selective KRAS inhibitors and the ongoing development of many more mutant-selective, pan-KRAS, and pan-RAS inhibitors. It details the promising early efficacy of these treatments across various cancer types, including NSCLC, CRC, and PDAC, but emphasizes the significant challenge posed by primary and acquired resistance. The article thoroughly examines genetic and non-genetic mechanisms of resistance, such as secondary KRAS mutations, RTK-RAS-MAPK pathway activation, and cell state changes like EMT, before outlining future opportunities for rational combination therapy strategies to overcome resistance and enhance the clinical impact of RAS-targeted treatments.
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