Oncogenic ras: From its activation to its direct targeting
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The RAS oncogenes are the most commonly mutated genes across human cancers. This review is a look back at the discovery of the RAS genes, how we came to understand their function, and how these oncogenes are aberrantly activated, driving cancer development and growth. It also highlights the comprehensive efforts made during the last 30 years to develop therapeutic strategies against the oncogenic mutant RAS. Although there have been many lost battles in the war against mutant RAS-bearing cancer cells, and we have yet to determine which is the “best” path for inhibition of the mutated RAS, a better understanding of the protein’s structure combined with technological advances in the field has allowed the development of new strategies to make anti-RAS therapies a reality. The state-of-the-art for each strategy is discussed, focusing on the promises and potential pitfalls of each of them.