2. Academic Validation
  3. Prostate cancer-associated SPOP mutations confer resistance to BET inhibitors through stabilization of BRD4

Prostate cancer-associated SPOP mutations confer resistance to BET inhibitors through stabilization of BRD4

  • Nat Med. 2017 Sep;23(9):1063-1071. doi: 10.1038/nm.4378.
Xiangpeng Dai 1,  Wenjian Gan 1,  Xiaoning Li 1 2,  Shangqian Wang 3,  Wei Zhang 4 5,  Ling Huang 6,  Shengwu Liu 7 8,  Qing Zhong 9,  Jianping Guo 1,  Jinfang Zhang 1,  Ting Chen 7 8,  Kouhei Shimizu 1,  Francisco Beca 1,  Mirjam Blattner 10,  Divya Vasudevan 10,  Dennis L Buckley 7 8,  Jun Qi 7 8,  Lorenz Buser 9,  Pengda Liu 1,  Hiroyuki Inuzuka 1,  Andrew H Beck 1,  Liewei Wang 11,  Peter J Wild 9,  Levi A Garraway 7,  Mark A Rubin 12 13,  Christopher E Barbieri 10,  Kwok-Kin Wong 7 8,  Senthil K Muthuswamy 6,  Jiaoti Huang 4,  Yu Chen 3,  James E Bradner 7 8,  Wenyi Wei 1
Affiliations

Affiliations

  • 1 Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
  • 2 Department of Pathophysiology, Basic Medical College, Jilin University, Changchun, China.
  • 3 Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
  • 4 Department of Pathology, Duke University School of Medicine, Durham, North Carolina, USA.
  • 5 Department of Pathology, Beijing Hospital, National Center of Gerontology, Beijing, China.
  • 6 Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
  • 7 Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
  • 8 Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
  • 9 Institute of Pathology and Molecular Pathology, University Hospital Zurich, Zurich, Switzerland.
  • 10 Department of Urology, Sandra and Edward Meyer Cancer Center, Weill Cornell Medical College, New York, New York, USA.
  • 11 Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, USA.
  • 12 Institute for Precision Medicine and Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York, USA.
  • 13 Sandra and Edward Meyer Cancer Center, Weill Cornell Medical College, New York, New York, USA.
PMID: 28805820 DOI: 10.1038/nm.4378
Abstract

The bromodomain and extraterminal (BET) family of proteins comprises four members-BRD2, BRD3, BRD4 and the testis-specific isoform BRDT-that largely function as transcriptional coactivators and play critical roles in various cellular processes, including the cell cycle, Apoptosis, migration and invasion. BET proteins enhance the oncogenic functions of major Cancer drivers by elevating the expression of these drivers, such as c-Myc in leukemia, or by promoting the transcriptional activities of oncogenic factors, such as AR and ERG in prostate Cancer. Pathologically, BET proteins are frequently overexpressed and are clinically linked to various types of human cancer; they are therefore being pursued as attractive therapeutic targets for selective inhibition in patients with Cancer. To this end, a number of bromodomain inhibitors, including JQ1 and I-BET, have been developed and have shown promising outcomes in early clinical trials. Although resistance to BET inhibitors has been documented in preclinical models, the molecular mechanisms underlying acquired resistance are largely unknown. Here we report that cullin-3SPOP earmarks BET proteins, including BRD2, BRD3 and BRD4, for ubiquitination-mediated degradation. Pathologically, prostate cancer-associated SPOP mutants fail to interact with and promote the degradation of BET proteins, leading to their elevated abundance in SPOP-mutant prostate Cancer. As a result, prostate Cancer cell lines and organoids derived from individuals harboring SPOP mutations are more resistant to BET-inhibitor-induced cell growth arrest and Apoptosis. Therefore, our results elucidate the tumor-suppressor role of SPOP in prostate Cancer in which it acts as a negative regulator of BET protein stability and also provide a molecular mechanism for resistance to BET inhibitors in individuals with prostate Cancer bearing SPOP mutations.

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