Neoplasia: An International Journal for Oncology Research (Mar 2019)
Characterizing the Therapeutic Potential of a Potent BET Degrader in Merkel Cell Carcinoma
- Jae Eun Choi,
- Monique E. Verhaegen,
- Sahr Yazdani,
- Rohit Malik,
- Paul W. Harms,
- Doris Mangelberger,
- Jean Tien,
- Xuhong Cao,
- Yuping Wang,
- Marcin Cieślik,
- Jonathan Gurkan,
- Mishaal Yazdani,
- Xiaojun Jing,
- Kristin Juckette,
- Fengyun Su,
- Rui Wang,
- Bing Zhou,
- Ingrid J. Apel,
- Shaomeng Wang,
- Andrzej A. Dlugosz,
- Arul M. Chinnaiyan
Affiliations
- Jae Eun Choi
- 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
- Monique E. Verhaegen
- Department of Dermatology, University of Michigan, Ann Arbor, MI, USA
- Sahr Yazdani
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, USA
- Rohit Malik
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, USA
- Paul W. Harms
- 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
- Doris Mangelberger
- Department of Dermatology, University of Michigan, Ann Arbor, MI, USA
- Jean Tien
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, USA
- Xuhong Cao
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, USA
- Yuping Wang
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, USA
- Marcin Cieślik
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, USA
- Jonathan Gurkan
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, USA
- Mishaal Yazdani
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, USA
- Xiaojun Jing
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, USA
- Kristin Juckette
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, USA
- Fengyun Su
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, USA
- Rui Wang
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, USA
- Bing Zhou
- 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
- Ingrid J. Apel
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, USA
- Shaomeng Wang
- 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
- Andrzej A. Dlugosz
- 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
- Arul M. Chinnaiyan
- 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; Address all correspondence to: Arul M. Chinnaiyan, Howard Hughes Medical Institute, Chevy Chase, MD, USA.
- Journal volume & issue
-
Vol. 21,
no. 3
pp. 322 – 330
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.