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Nat Med. 2017 Sep;23(9):1055-1062. doi: 10.1038/nm.4379. Epub 2017 Aug 14.

Intrinsic BET inhibitor resistance in SPOP-mutated prostate cancer is mediated by BET protein stabilization and AKT-mTORC1 activation.

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State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China.
Fudan University Shanghai Cancer Center and Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
Department of Urology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.
Department of Gastroenterology, Jiangxi Institute of Gastroenterology and Hepatology, First Affiliated Hospital of Nanchang University, Nanchang, China.
Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.
Department of Urology, Shanghai Changhai Hospital, Second Military Medical University, Shanghai, China.
Division of Biomedical Statistics and Informatics, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.
Department of Pathology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, China.
Department of Experimental Therapeutics, BC Cancer Research Centre, Vancouver, British Columbia, Canada.
Mayo Clinic Cancer Center, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.


Bromodomain and extraterminal domain (BET) protein inhibitors are emerging as promising anticancer therapies. The gene encoding the E3 ubiquitin ligase substrate-binding adaptor speckle-type POZ protein (SPOP) is the most frequently mutated in primary prostate cancer. Here we demonstrate that wild-type SPOP binds to and induces ubiquitination and proteasomal degradation of BET proteins (BRD2, BRD3 and BRD4) by recognizing a degron motif common among them. In contrast, prostate cancer-associated SPOP mutants show impaired binding to BET proteins, resulting in decreased proteasomal degradation and accumulation of these proteins in prostate cancer cell lines and patient specimens and causing resistance to BET inhibitors. Transcriptome and BRD4 cistrome analyses reveal enhanced expression of the GTPase RAC1 and cholesterol-biosynthesis-associated genes together with activation of AKT-mTORC1 signaling as a consequence of BRD4 stabilization. Our data show that resistance to BET inhibitors in SPOP-mutant prostate cancer can be overcome by combination with AKT inhibitors and further support the evaluation of SPOP mutations as biomarkers to guide BET-inhibitor-oriented therapy in patients with prostate cancer.

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