期刊
NATURE COMMUNICATIONS
卷 13, 期 1, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41467-022-28801-y
关键词
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资金
- American Cancer Society [130042-IRG-16-244-10-IRG]
- Melanoma Research Foundation and Legacy of Hope Merit Award
- NIH/NCI [R01 (CA196278), R01 CA232256, S10ODO23666]
- Department of Defense [CA171056]
- Dr. Miriam and Sheldon G. Adelson Medical Research Foundation awards
- Melanoma Research Alliance Award [568992]
- National Cancer Center Support Grant [P30 CA056036]
- Cancer Center Support Grant [CA010815]
- Comprehensive Cancer Center Grant NCI [P30 CA06927]
- [P01 CA114046-11A1]
Cellular plasticity plays a crucial role in tumor heterogeneity and phenotype switching. SOX10 is involved in the phenotypic switching of cutaneous melanoma, and cIAP1/2 inhibitors can selectively induce cell death in SOX10-deficient cells.
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. Mechanisms underlying tumor cell plasticity remain poorly understood. Here, the authors show the presence of a dormant-invasive SOX10- subpopulation in cutaneous melanoma that can be targeted by cIAP1/2 inhibitors.
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