Loss of the tumor suppressor gene CDKN2A, encoding p16 and p14, is a frequent event driving melanoma progression. Therefore, therapeutic strategies aimed at CDKN2A loss hold great potential to improve melanoma treatment. Pharmacological inhibition of the p16 targets CDK4/6 is a prime example of such a strategy. Other approaches exploit cell cycle deregulation, target metabolic rewiring, epigenetically restore expression, act on dependencies resulting from co-deleted genes, or are directed at the effects of CDKN2A loss on immune responses. This review explores these therapeutic strategies targeting CDKN2A loss, which potentially open up new avenues for precision medicine in melanoma.
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