Abstract P070: Targeting SOX10 deficient cells to reduce resistance to targeted therapy in melanoma

Abstract

Abstract Cellular plasticity contributes to intra-tumoral heterogeneity and phenotype switching, traits that enable tumor cell adaptation to metastatic microenvironments and resistance to targeted therapies. Despite these wide-ranging effects, the key mechanisms that underlie tumor cell plasticity remain poorly understood. We studied the role of SOX10, a neural crest lineage transcription factor, and its role in cutaneous melanoma plasticity. SOX10 was heterogeneously expressed in melanoma patient samples. Loss of SOX10 was sufficient to induce a slow cell cycling phenotype in vitro and in vivo, which was associated with invasive properties including expression of mesenchymal genes and extracellular matrix, as well as tolerance to BRAF and/or MEK inhibitors. Long-term exposure of co-mixtures of SOX10-proficient and SOX10-deficient cells to targeted therapy selected for SOX10 knockout cells. Furthermore, cell lines generated from BRAF-MEK inhibitor resistant xenografts showed dramatic reductions in SOX10 expression. To identify synthetic lethal interactions with SOX10 loss, we screened a drug compound library and identified the class of cellular inhibitor of apoptosis protein-1/2 (cIAP1/2) inhibitors as selectively inducing cell death in SOX10-deficient cells. Combining cIAP1/2 inhibitor with BRAF/MEK inhibitors delayed the onset of acquired resistance in melanomas in vivo. Together, 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 novel strategy by selectively eliminating SOX10-deficient cells. Citation Format: Claudia Capparelli, Timothy Purwin, Andrew Aplin. Targeting SOX10 deficient cells to reduce resistance to targeted therapy in melanoma [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P070.