Altogether, these results underscore the importance of the MAPK pathway in driving intrinsic and acquired CDK4i/6i resistance in ALM and the translational potential of MEKi to increase the in vivo antitumor activity of CDK4i/6i against therapy naïve and CDK4i/6i-resistant ALMs, via increased DNA damage, cell arrest and tumor cell death (Fig. 4K). This evidence concerns the gene CDKN2A and acral lentiginous melanoma.