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

  • Janouskova H Institute of Oncology Research, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.
  • El Tekle G Institute of Oncology Research, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.
  • Bellini E Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland
  • Udeshi ND Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
  • Rinaldi A Institute of Oncology Research, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.
  • Ulbricht A Department of Biochemistry, Eidgenössische Technische Hochschule, Zurich, Switzerland.
  • Bernasocchi T Institute of Oncology Research, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.
  • Civenni G Institute of Oncology Research, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.
  • Losa M Institute of Oncology Research, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.
  • Svinkina T Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
  • Bielski CM Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
  • Kryukov GV Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
  • Cascione L Institute of Oncology Research, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.
  • Napoli S Institute of Oncology Research, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.
  • Enchev RI Department of Biochemistry, Eidgenössische Technische Hochschule, Zurich, Switzerland.
  • Mutch DG Division of Gynecologic Oncology, Washington University, St. Louis, Missouri, USA.
  • Carney ME Department of Obstetrics, Gynecology and Women’s Health, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, Hawaii, USA.
  • Berchuck A Division of Gynecologic Oncology, Duke Cancer Center, Durham, North Carolina, USA.
  • Winterhoff BJN Division of Gynecologic Oncology, University of Minnesota, Minneapolis, Minnesota, USA.
  • Broaddus RR Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
  • Schraml P Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland
  • Moch H Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland
  • Bertoni F Institute of Oncology Research, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.
  • Catapano CV Institute of Oncology Research, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.
  • Peter M Department of Biochemistry, Eidgenössische Technische Hochschule, Zurich, Switzerland.
  • Carr SA Department of Biochemistry, Eidgenössische Technische Hochschule, Zurich, Switzerland.
  • Garraway LA Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
  • Wild PJ Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland
  • Theurillat JP Institute of Oncology Research, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.
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  • 2017-08-15
Published in:
  • Nature medicine. - 2017
Acetanilides
Adenocarcinoma, Clear Cell
Animals
Apoptosis
Azepines
Carcinoma, Endometrioid
Carcinosarcoma
Cell Cycle Proteins
Cell Line, Tumor
Cell Proliferation
Chromatography, Liquid
Cullin Proteins
Drug Resistance, Neoplasm
Endometrial Neoplasms
Epigenesis, Genetic
Female
Heterocyclic Compounds, 3-Ring
Humans
Immunoblotting
Immunohistochemistry
Immunoprecipitation
Male
Mass Spectrometry
Mice, Nude
Molecular Targeted Therapy
Mutation
Neoplasm Transplantation
Neoplasms, Cystic, Mucinous, and Serous
Nuclear Proteins
Prostatic Neoplasms
Protein-Serine-Threonine Kinases
RNA-Binding Proteins
Repressor Proteins
Reverse Transcriptase Polymerase Chain Reaction
Transcription Factors
Triazoles
Ubiquitination
English 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.
Language
  • English
Open access status
green
Identifiers
Persistent URL
https://sonar.ch/global/documents/199413
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