Targeting SOX10-deficient cells to reduce the dormant-invasive phenotype state in melanoma

Claudia Capparelli, Timothy J. Purwin, McKenna K. Glasheen, Signe Caksa, Manoela Tiago, Nicole Wilski, Danielle Pomante, Sheera Rosenbaum, Mai Q. Nguyen, Weijia Cai, Janusz Franco-Barraza, Richard Zheng, Gaurav Kumar, Inna Chervoneva, Ayako Shimada, Vito W. Rebecca, Adam E. Snook, Kim Hookim, Xiaowei Xu, Edna CukiermanMeenhard Herlyn, Andrew E. Aplin

Research output: Contribution to journalArticlepeer-review


Cellular plasticity contributes to intra-tumoral heterogeneity and phenotype switching, which enable adaptation to metastatic microenvironments and resistance to therapies. Mechanisms underlying tumor cell plasticity remain poorly understood. SOX10, a neural crest lineage transcription factor, is heterogeneously expressed in melanomas. Loss of SOX10 reduces proliferation, leads to invasive properties, including the expression of mesenchymal genes and extracellular matrix, and promotes tolerance to BRAF and/or MEK inhibitors. We identify the class of cellular inhibitor of apoptosis protein-1/2 (cIAP1/2) inhibitors as inducing cell death selectively in SOX10-deficient cells. Targeted therapy selects for SOX10 knockout cells underscoring their drug tolerant properties. Combining cIAP1/2 inhibitor with BRAF/MEK inhibitors delays the onset of acquired resistance in melanomas in vivo. These data suggest that SOX10 mediates phenotypic switching in cutaneous melanoma to produce a targeted inhibitor tolerant state that is likely a prelude to the acquisition of resistance. Furthermore, we provide a therapeutic strategy to selectively eliminate SOX10-deficient cells.

Original languageEnglish (US)
Article number1381
JournalNature communications
Issue number1
StatePublished - Dec 2022

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • General
  • Physics and Astronomy(all)


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