2. Academic Validation
  3. Modelling Acral Melanoma in Admixed Brazilians Uncovers Genomic Drivers and Targetable Pathways

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

  • medRxiv. 2025 Aug 13:2025.08.08.25332963. doi: 10.1101/2025.08.08.25332963.
Annie Cristhine Moraes Sousa-Squiavinato 1,  Sara Santos Bernardes 2,  Flávia C Aguiar 1,  Antonio C Facciolo 1 3,  Martín Del Castillo Velasco Herrera 3,  J Rene C Wong-Ramirez 4 5,  Patricia Basurto-Lozada 5,  Aretha Brito Nobre 6,  Geethanjali Annamalai 7,  Rebecca Martins Cadimo do Nascimento 1,  Jacqueline Boccacino 3,  Rafaela Fagundes 3,  Pedro Sodré do R Barros 1,  Mariana de Moraes Pitombo 1,  Rebeca Olvera-León 3,  Larissa Satiko Alcantara Sekimoto Matsuyama 3,  Jamie Billington 3,  Ian Vermes 3,  Irving Simonin-Wilmer 5,  Danielle G Carvalho 1,  João Pedro Cavalcante Simoes 1,  Priscila Valverde Fernandes 6,  Luiz Fernando Nunes 8,  Andreia Cristina de Melo 9,  Jadivan Leite de Oliveira 8,  Meenhard Herlyn 10,  Andrew E Aplin 7 11,  Carla Daniela Robles-Espinoza 5,  David J Adams 3,  Patricia A Possik 1 3
Affiliations

Affiliations

  • 1 Division of Basic and Experimental Research, Brazilian National Cancer Institute, Rua Andre Cavalcanti 37, Rio de Janeiro, 20231-050, Brazil.
  • 2 Tissue Microenvironment Laboratory, Department of Pathology, Federal University of Minas Gerais, Belo Horizonte, Brazil.
  • 3 Wellcome Sanger Institute, Hinxton, CB10 1SA, UK.
  • 4 Research Program in Systems Oncology, University of Helsinki, Helsinki, 00100, Finland.
  • 5 Laboratorio Internacional de Investigación sobre el Genoma Humano, Universidad Nacional Autónoma de México, Santiago de Querétaro, 76230, México.
  • 6 Division of Human Pathology, Brazilian National Cancer Institute, Rua Cordeiro da Graça, 156, Rio de Janeiro, 20220-400, Brazil.
  • 7 Sidney Kimmel Comprehensive Cancer Center, Thomas Jefferson University, Philadelphia, USA.
  • 8 Hospital de Câncer II, Brazilian National Cancer Institute, Avenida Via Binário do Porto, 831, Rio de Janeiro, 20081-250, Brazil.
  • 9 Division of Clinical Research and Technological Development, Brazilian National Cancer Institute, Rua Andre Cavalcanti 37, Rio de Janeiro, 20231-050, Brazil.
  • 10 Melanoma Research Center, Wistar Institute, Philadelphia, USA.
  • 11 Department of Pharmacology, Physiology and Cancer Biology, Thomas Jefferson University, Philadelphia, USA.
PMID: 40832384 DOI: 10.1101/2025.08.08.25332963
Abstract

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.

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