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Nat Med. 2017 Sep;23(9):1046-1054. doi: 10.1038/nm.4372. Epub 2017 Aug 14.

Opposing effects of cancer-type-specific SPOP mutants on BET protein degradation and sensitivity to BET inhibitors.

Author information

1
Institute of Oncology Research, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.
2
Faculty of Biomedical Science, Università della Svizzera Italiana, Lugano, Switzerland.
3
Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland.
4
Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland
5
Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
6
Department of Biochemistry, Eidgenössische Technische Hochschule, Zurich, Switzerland.
7
Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
8
Division of Gynecologic Oncology, Washington University, St. Louis, Missouri, USA.
9
Department of Obstetrics, Gynecology and Women’s Health, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, Hawaii, USA.
10
Division of Gynecologic Oncology, Duke Cancer Center, Durham, North Carolina, USA.
11
Division of Gynecologic Oncology, University of Minnesota, Minneapolis, Minnesota, USA.
12
Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
#
Contributed equally

Abstract

It is generally assumed that recurrent mutations within a given cancer driver gene elicit similar drug responses. Cancer genome studies have identified recurrent but divergent missense mutations affecting the substrate-recognition domain of the ubiquitin ligase adaptor SPOP in endometrial and prostate cancers. The therapeutic implications of these mutations remain incompletely understood. Here we analyzed changes in the ubiquitin landscape induced by endometrial cancer-associated SPOP mutations and identified BRD2, BRD3 and BRD4 proteins (BETs) as SPOP-CUL3 substrates that are preferentially degraded by endometrial cancer-associated SPOP mutants. The resulting reduction of BET protein levels sensitized cancer cells to BET inhibitors. Conversely, prostate cancer-specific SPOP mutations resulted in impaired degradation of BETs, promoting their resistance to pharmacologic inhibition. These results uncover an oncogenomics paradox, whereby mutations mapping to the same domain evoke opposing drug susceptibilities. Specifically, we provide a molecular rationale for the use of BET inhibitors to treat patients with endometrial but not prostate cancer who harbor SPOP mutations.

PMID:
28805821
PMCID:
PMC5592092
DOI:
10.1038/nm.4372
[Indexed for MEDLINE]
Free PMC Article

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