Characterizing the Therapeutic Potential of a Potent BET Degrader in Merkel Cell Carcinoma
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 s...
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| Format: | Article |
| Language: | English |
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Elsevier
2019-03-01
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| Series: | Neoplasia: An International Journal for Oncology Research |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1476558618305323 |
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Article |
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DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
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 |
| spellingShingle |
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 Characterizing the Therapeutic Potential of a Potent BET Degrader in Merkel Cell Carcinoma Neoplasia: An International Journal for Oncology Research |
| author_facet |
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 |
| author_sort |
Jae Eun Choi |
| title |
Characterizing the Therapeutic Potential of a Potent BET Degrader in Merkel Cell Carcinoma |
| title_short |
Characterizing the Therapeutic Potential of a Potent BET Degrader in Merkel Cell Carcinoma |
| title_full |
Characterizing the Therapeutic Potential of a Potent BET Degrader in Merkel Cell Carcinoma |
| title_fullStr |
Characterizing the Therapeutic Potential of a Potent BET Degrader in Merkel Cell Carcinoma |
| title_full_unstemmed |
Characterizing the Therapeutic Potential of a Potent BET Degrader in Merkel Cell Carcinoma |
| title_sort |
characterizing the therapeutic potential of a potent bet degrader in merkel cell carcinoma |
| publisher |
Elsevier |
| series |
Neoplasia: An International Journal for Oncology Research |
| issn |
1476-5586 |
| publishDate |
2019-03-01 |
| description |
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. |
| url |
http://www.sciencedirect.com/science/article/pii/S1476558618305323 |
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doaj-7a5b331b6f5c4acf900c39277f84e9212020-11-24T22:07:58ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55862019-03-01213322330Characterizing the Therapeutic Potential of a Potent BET Degrader in Merkel Cell CarcinomaJae Eun Choi0Monique E. Verhaegen1Sahr Yazdani2Rohit Malik3Paul W. Harms4Doris Mangelberger5Jean Tien6Xuhong Cao7Yuping Wang8Marcin Cieślik9Jonathan Gurkan10Mishaal Yazdani11Xiaojun Jing12Kristin Juckette13Fengyun Su14Rui Wang15Bing Zhou16Ingrid J. Apel17Shaomeng Wang18Andrzej A. Dlugosz19Arul M. Chinnaiyan20Michigan 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, USADepartment of Dermatology, University of Michigan, Ann Arbor, MI, USAMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, USAMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, USAMichigan 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, USADepartment of Dermatology, University of Michigan, Ann Arbor, MI, USAMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, USAMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, USAMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, USAMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, USAMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, USAMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, USAMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, USAMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, USAMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, USAMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, USAMichigan 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, USAMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, USARogel 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, USADepartment 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, USAMichigan 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.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.http://www.sciencedirect.com/science/article/pii/S1476558618305323 |