Modelling Acral Melanoma in Admixed Brazilians Uncovers Genomic Drivers and Targetable Pathways.

Acral melanoma (AM) is an aggressive melanoma subtype with limited therapeutic options and poor outcomes. In non-European descent and admixed populations, like those residing in Latin America, AM accounts for a significant proportion of cutaneous melanoma cases. Here, we performed comprehensive genomic and functional profiling of AM from a uniquely diverse Brazilian cohort. Whole-exome and transcriptome sequencing revealed low mutation burden and predominance of copy number alterations, including high-amplitude focal amplifications termed hailstorms. These hailstorms frequently affected chromosomes 11, 5 and 22 and key oncogenes such as CCND1, GAB2, CDK4, and TERT. The presence of hailstorms in the long arms of chromosomes 11 and 22 was associated with higher focal copy number burden and loss of DNA damage response genes (ATM, CHEK1), suggesting a permissive genomic environment driving structural instability. To explore the unique genomic context of AM, we established a comprehensive collection of patient-derived xenograft (AM-PDX) models that faithfully retain the histopathological and genomic features of the original tumours. Functional exploration of AM-specific vulnerabilities through pharmacological and CRISPR/Cas9 knockout screenings identified strong sensitivity to targeting MAPK, CDK4/6, MDM2, and WEE1 pathways. Notably, the pan-RAS(ON) inhibitor RMC-7977 effectively reduced viability in NRAS-, KRAS-, and KIT-mutant AM cell lines. Finally, CRISPR screens revealed dependencies selectively essential in AM, including CRKL and SF3B4, highlighting previously unrecognized vulnerabilities. Our findings emphasize the distinct biology of AM compared to other subtypes of melanoma, provide a valuable resource of models reflective of Latin American ancestry, and identify potential drivers and therapeutic targets.