Acral melanoma (AM) is a rare and aggressive melanoma subtype that arises on sun-shielded areas of the skin and is distinct from cutaneous melanoma (CM) both genomically and clinically. AM is driven primarily by complex structural variants rather than canonical point mutations, resulting in low tumor mutational burden, high chromosomal instability, and a lack of effective targeted therapies. The aim of this dissertation was to identify novel therapeutic vulnerabilities in AM by leveraging mechanistic insights and drug sensitivities observed in other neural crest-derived malignancies, including neuroblastoma and glioma. These tumor types, like AM, exhibit epigenetic dysregulation, low mutational burden, and frequent chromosomal rearrangements, guiding our interest in epigenetic-targeting strategies. We investigated the effects of GSK-J4, a histone demethylase inhibitor, across a panel of genomically diverse AM cell lines. GSK-J4 significantly reduced viability of AM cells by inducing G1 cell cycle arrest and impairing clonogenic capacity regardless of MAPK mutational status. Mechanistically, GSK-J4 upregulated ER stress response markers ATF4, CHOP, and spliced XBP1, promoting cell death through a PERK-dependent axis. GSK-J4 also delayed tumor progression and prolonged survival in an AM xenograft model. To enhance therapeutic efficacy, we explored combinations with the novel small-molecule S6K2 inhibitor, CD02. Both GSK-J4 and CD02 synergistically suppressed viability and induced cell death in several AM models. Mechanistic studies revealed that CD02 and GSK-J4 cooperatively activated ER stress and downregulated the proto-oncogenic adaptor protein IRS4. Genetic depletion of IRS4 independently induced cell death, identifying it as a potential therapeutic vulnerability in AM. Collectively, this work highlights the therapeutic potential of GSK-J4 as a single agent or in combination with CD02 in AM. These findings support further preclinical development of GSK-J4 as a promising strategy for the treatment of AM, particularly given its ability to overcome genomic diversity and activate conserved stress response pathways.