Dataset Information

Targeting Upregulated cIAP2 in SOX10-Deficient Drug Tolerant Melanoma.

ABSTRACT: Drug tolerance and minimal residual disease (MRD) are likely to prelude acquired resistance to targeted therapy. Mechanisms that allow persister cells to survive in the presence of targeted therapy are being characterized but selective vulnerabilities for these subpopulations remain uncertain. We identified cellular inhibitor of apoptosis protein 2 (cIAP2) as being highly expressed in SOX10-deficient drug tolerant persister (DTP) melanoma cells. Here, we show that cIAP2 is sufficient to induce tolerance to MEK inhibitors, likely by decreasing the levels of cell death. Mechanistically, cIAP2 is upregulated at the transcript level in SOX10-deficient cells and the AP-1 complex protein, JUND, is required for its expression. Using a patient-derived xenograft model, we demonstrate that treatment with the cIAP1/2 inhibitor, birinapant, during the MRD phase delays the onset of resistance to BRAF inhibitor and MEK inhibitor combination therapy. Together, our data suggest that cIAP2 upregulation in SOX10-deficient subpopulations of melanoma cells induces drug tolerance to MAPK targeting agents and provides a rationale to test a novel therapeutical approach to target MRD.

SUBMITTER: Glasheen MQ

PROVIDER: S-EPMC10527992 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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Targeting Upregulated cIAP2 in SOX10-Deficient Drug Tolerant Melanoma.

Glasheen McKenna Q MQ Caksa Signe S Young Amelia G AG Wilski Nicole A NA Ott Connor A CA Chervoneva Inna I Flaherty Keith T KT Herlyn Meenhard M Xu Xiaowei X Aplin Andrew E AE Capparelli Claudia C

Molecular cancer therapeutics 20230901 9

Drug tolerance and minimal residual disease (MRD) are likely to prelude acquired resistance to targeted therapy. Mechanisms that allow persister cells to survive in the presence of targeted therapy are being characterized but selective vulnerabilities for these subpopulations remain uncertain. We identified cellular inhibitor of apoptosis protein 2 (cIAP2) as being highly expressed in SOX10-deficient drug tolerant persister (DTP) melanoma cells. Here, we show that cIAP2 is sufficient to induce t ...[more]

PMID: 37343247

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Project description:Recent studies indicate that the development of drug resistance and increased invasiveness in melanoma is largely driven by transcriptional plasticity rather than canonical coding mutations. Understanding the mechanisms behind cell identity shifts in oncogenic transformation and cancer progression is crucial for advancing our understanding of melanoma and other aggressive cancers. While distinct melanoma phenotypic states have been well characterized, the processes and transcriptional controls that enable cells to shift between these states remain largely unknown. In this study, we initially leverage the well-established zebrafish melanoma model as a high-throughput system to dissect and analyze transcriptional control elements that are hijacked by melanoma. We identify key characteristics of these elements, making them translatable to human enhancer identification despite the lack of direct sequence conservation. Building on our identification of a zebrafish sox10 enhancer necessary for melanoma initiation, we extend these findings to human melanoma, identifying two human upstream enhancer elements that are critical for full SOX10 expression. Stable biallelic deletion of these enhancers using CRISPR-Cas9 induces a distinct phenotype shift across multiple human melanoma cell lines from a melanocytic phenotype towards an undifferentiated phenotype and is also characterized by an increase in drug resistance that mirrors clinical data including an upregulation of NTRK1, a tyrosine kinase, and potential therapeutic target. These results provide new insights into the transcriptional regulation of SOX10 in human melanoma and underscore the role of individual enhancer elements and potentially NTRK1 in driving melanoma phenotype plasticity and drug resistance. Our work lays the groundwork for future gene-based and combination kinase-inhibitor therapies targeting SOX10 regulation and NTRK1 as a potential avenue for enhancing the efficacy of current melanoma treatments.

Dataset Information

Targeting Upregulated cIAP2 in SOX10-Deficient Drug Tolerant Melanoma.

Publications

Targeting Upregulated cIAP2 in SOX10-Deficient Drug Tolerant Melanoma.

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