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

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

doi:10.1038/s41467-022-28801-y

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.

Highlights

Cellular plasticity contributes to intra-tumoral heterogeneity and phenotype switching, which enable adaptation to metastatic microenvironments and resistance to therapies
Heterogeneity and plasticity are evident in cutaneous melanoma and are associated with non-responsiveness and acquired resistance to pharmacological inhibitors of the BRAFMEK signaling pathway and to immune checkpoint antibodies such as anti-PD1 and anti-CTLA42–4
Consistent with the cell line-derived RNA-seq data (Fig. 2c, d and Supplementary Fig. 1A–H and 4G–I), Gene Set Enrichment Analysis (GSEA) analysis showed that resistant tumors lacking SOX10 or with a SOX10-deficient transcriptomic profile displayed enrichment in genes involved in epithelial-mesenchymal transition (EMT), hypoxia, TGFβ signaling, apical junction, angiogenesis, TNFA signaling via NFκB, glycolysis, and extracellular structure organization (Fig. 5h and Supplementary Fig. 4N)

Summary

Results

Consistent with the cell line-derived RNA-seq data (Fig. 2c, d and Supplementary Fig. 1A–H and 4G–I), GSEA analysis showed that resistant tumors lacking SOX10 or with a SOX10-deficient transcriptomic profile displayed enrichment in genes involved in EMT, hypoxia, TGFβ signaling, apical junction, angiogenesis, TNFA signaling via NFκB, glycolysis, and extracellular structure organization (Fig. 5h and Supplementary Fig. 4N). Consistent with reduced G1/S progression, RB1 phosphorylation was decreased and p27Kip[1] expression was increased following BRAFi + MEKi treatment of CRT lines (Supplementary Fig. 4P) These data indicate that a drug-tolerant SOX10-negative population often arises following the treatment of melanoma with BRAFi and/or MEKi, and that this might be the population of cells that seeds tumor recurrence. These data support the notion that targeting the SOX10-negative subpopulation improves the durable efficacy of BRAFi+MEKi

Discussion

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Code availability