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Choi, Jae Eun; Verhaegen, Monique E.; Yazdani, Sahr; Malik, Rohit; Harms, Paul W.; Mangelberger, Doris; Tien, Jean; Cao, Xuhong; Wang, Yuping; Cieslik, Marcin; Gurkan, Jonathan; Yazdani, Mishaal; Jing, Xiaojun; Juckette, Kristin; Su, Fengyun; Wang, Rui; Zhou, Bing; Apel, Ingrid J.; Wang, Shaomeng; Dlugosz, Andrzej A. and Chinnaiyan, Arul M. (2019): Characterizing the Therapeutic Potential of a Potent BET Degrader in Merkel Cell Carcinoma. In: Neoplasia, Vol. 21, No. 3: pp. 322-330

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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.

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