1. Characterizing the Therapeutic Potential of a Potent BET Degrader in Merkel Cell Carcinoma.
- Author
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Choi JE, Verhaegen ME, Yazdani S, Malik R, Harms PW, Mangelberger D, Tien J, Cao X, Wang Y, Cieślik M, Gurkan J, Yazdani M, Jing X, Juckette K, Su F, Wang R, Zhou B, Apel IJ, Wang S, Dlugosz AA, and Chinnaiyan AM
- Subjects
- Acetanilides pharmacology, Antigens, Viral, Tumor genetics, Antigens, Viral, Tumor metabolism, Carcinoma, Merkel Cell drug therapy, Carcinoma, Merkel Cell etiology, Carcinoma, Merkel Cell pathology, Cell Cycle genetics, Cell Line, Tumor, Dose-Response Relationship, Drug, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Genes, Homeobox, Heterocyclic Compounds, 3-Ring pharmacology, Humans, Merkel cell polyomavirus physiology, Polyomavirus Infections complications, Polyomavirus Infections virology, Proteolysis, Skin Neoplasms drug therapy, Skin Neoplasms etiology, Skin Neoplasms pathology, Transcriptome, Carcinoma, Merkel Cell metabolism, Proteins antagonists & inhibitors, Proteins metabolism, Skin Neoplasms metabolism
- Abstract
Studies on the efficacy of small molecule inhibitors in Merkel cell carcinoma (MCC) have been limited and largely inconclusive. In this study, we investigated the therapeutic potential of a potent BET degrader, BETd-246, in the treatment of MCC. We found that MCC cell lines were significantly more sensitive to BETd-246 than to BET inhibitor treatment. Therapeutic targeting of BET proteins resulted in a loss of "MCC signature" genes but not MYC expression as previously described irrespective of Merkel cell polyomavirus (MCPyV) status. In MCPyV+ MCC cells, BETd-246 alone suppressed downstream targets in the MCPyV-LT Ag axis. We also found enrichment of HOX and cell cycle genes in MCPyV- MCC cell lines that were intrinsically resistant to BETd-246. Our findings uncover a requirement for BET proteins in maintaining MCC lineage identity and point to the potential utility of BET degraders for treating MCC., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2019
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