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Neoplasia. 2019 Mar;21(3):322-330. doi: 10.1016/j.neo.2019.01.003. Epub 2019 Feb 21.

Characterizing the Therapeutic Potential of a Potent BET Degrader in Merkel Cell Carcinoma.

Author information

1
Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Cancer Biology Program, University of Michigan, Ann Arbor, MI, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
2
Department of Dermatology, University of Michigan, Ann Arbor, MI, USA.
3
Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
4
Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Dermatology, University of Michigan, Ann Arbor, MI, USA.
5
Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA; Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI, USA.
6
Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA; Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA; Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA; Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI, USA.
7
Department of Dermatology, University of Michigan, Ann Arbor, MI, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA; Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI, USA.
8
Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA; Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI, USA; Howard Hughes Medical Institute, Chevy Chase, MD, USA; Department of Urology, University of Michigan, Ann Arbor, MI, USA. Electronic address: arul@med.umich.edu.

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.

PMID:
30797188
PMCID:
PMC6384317
DOI:
10.1016/j.neo.2019.01.003
[Indexed for MEDLINE]
Free PMC Article

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