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

Claudia Capparelli (), Timothy J. Purwin, McKenna 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 Cukierman, Meenhard Herlyn and Andrew E. Aplin ()
Additional contact information
Claudia Capparelli: Thomas Jefferson University
Timothy J. Purwin: Thomas Jefferson University
McKenna Glasheen: Thomas Jefferson University
Signe Caksa: Thomas Jefferson University
Manoela Tiago: Thomas Jefferson University
Nicole Wilski: Thomas Jefferson University
Danielle Pomante: Thomas Jefferson University
Sheera Rosenbaum: Thomas Jefferson University
Mai Q. Nguyen: Thomas Jefferson University
Weijia Cai: Thomas Jefferson University
Janusz Franco-Barraza: Fox Chase Cancer Center
Richard Zheng: Thomas Jefferson University
Gaurav Kumar: Thomas Jefferson University
Inna Chervoneva: Thomas Jefferson University
Ayako Shimada: Thomas Jefferson University
Vito W. Rebecca: The Wistar Institute
Adam E. Snook: Thomas Jefferson University
Kim Hookim: Thomas Jefferson University
Xiaowei Xu: Perelman School of Medicine, University of Pennsylvania
Edna Cukierman: Fox Chase Cancer Center
Meenhard Herlyn: The Wistar Institute
Andrew E. Aplin: Thomas Jefferson University

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-28801-y

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