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

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.

SUBMITTER: Choi JE

PROVIDER: S-EPMC6384317 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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

Choi Jae Eun JE Verhaegen Monique E ME Yazdani Sahr S Malik Rohit R Harms Paul W PW Mangelberger Doris D Tien Jean J Cao Xuhong X Wang Yuping Y Cieślik Marcin M Gurkan Jonathan J Yazdani Mishaal M Jing Xiaojun X Juckette Kristin K Su Fengyun F Wang Rui R Zhou Bing B Apel Ingrid J IJ Wang Shaomeng S Dlugosz Andrzej A AA Chinnaiyan Arul M AM

Neoplasia (New York, N.Y.) 20190221 3

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 M ...[more]

PMID: 30797188

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Project description:OPINION STATEMENT:Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine tumor of the skin. Early-stage disease can be cured with surgical resection and radiotherapy (RT). Sentinel lymph node biopsy (SLNB) is an important staging tool, as a microscopic MCC is frequently identified. Adjuvant RT to the primary excision site and regional lymph node bed may improve locoregional control. However, newer studies confirm that patients with biopsy-negative sentinel lymph nodes may not benefit from regional RT. Advanced MCC currently lacks a highly effective treatment as responses to chemotherapy are not durable. Recent work suggests that immunotherapy targeting the programmed cell death receptor 1/programmed cell death ligand 1 (PD-1/PD-L1) checkpoint holds great promise in treating advanced MCC and may provide durable responses in a portion of patients. At the same time, high-throughput sequencing studies have demonstrated significant differences in the mutational profiles of tumors with and without the Merkel cell polyomavirus (MCV). An important secondary endpoint in the ongoing immunotherapy trials for MCC will be determining if there is a response difference between the virus-positive MCC tumors that typically lack a large mutational burden and the virus-negative tumors that have a large number of somatic mutations and predicted tumor neoantigens. Interestingly, sequencing studies have failed to identify a highly recurrent activated driver pathway in the majority of MCC tumors. This may explain why targeted therapies can demonstrate exceptional responses in case reports but fail when treating all comers with MCC. Ultimately, a precision medicine approach may be more appropriate for treating MCC, where identified driver mutations are used to direct targeted therapies. At a minimum, stratifying patients in future clinical trials based on tumor viral status should be considered as virus-negative tumors are more likely to harbor activating driver mutations.

Dataset Information

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

Publications

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

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