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

Publication ,  Journal Article
Janouskova, H; El Tekle, G; Bellini, E; Udeshi, ND; Rinaldi, A; Ulbricht, A; Bernasocchi, T; Civenni, G; Losa, M; Svinkina, T; Bielski, CM ...
Published in: Nat Med
September 2017

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.

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Published In

Nat Med

DOI

EISSN

1546-170X

Publication Date

September 2017

Volume

23

Issue

9

Start / End Page

1046 / 1054

Location

United States

Related Subject Headings

  • Ubiquitination
  • Triazoles
  • Transcription Factors
  • Reverse Transcriptase Polymerase Chain Reaction
  • Repressor Proteins
  • RNA-Binding Proteins
  • Protein Serine-Threonine Kinases
  • Prostatic Neoplasms
  • Nuclear Proteins
  • Neoplasms, Cystic, Mucinous, and Serous
 

Citation

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Janouskova, H., El Tekle, G., Bellini, E., Udeshi, N. D., Rinaldi, A., Ulbricht, A., … Theurillat, J.-P. (2017). Opposing effects of cancer-type-specific SPOP mutants on BET protein degradation and sensitivity to BET inhibitors. Nat Med, 23(9), 1046–1054. https://doi.org/10.1038/nm.4372
Janouskova, Hana, Geniver El Tekle, Elisa Bellini, Namrata D. Udeshi, Anna Rinaldi, Anna Ulbricht, Tiziano Bernasocchi, et al. “Opposing effects of cancer-type-specific SPOP mutants on BET protein degradation and sensitivity to BET inhibitors.Nat Med 23, no. 9 (September 2017): 1046–54. https://doi.org/10.1038/nm.4372.
Janouskova H, El Tekle G, Bellini E, Udeshi ND, Rinaldi A, Ulbricht A, et al. Opposing effects of cancer-type-specific SPOP mutants on BET protein degradation and sensitivity to BET inhibitors. Nat Med. 2017 Sep;23(9):1046–54.
Janouskova, Hana, et al. “Opposing effects of cancer-type-specific SPOP mutants on BET protein degradation and sensitivity to BET inhibitors.Nat Med, vol. 23, no. 9, Sept. 2017, pp. 1046–54. Pubmed, doi:10.1038/nm.4372.
Janouskova H, El Tekle G, Bellini E, Udeshi ND, Rinaldi A, Ulbricht A, Bernasocchi T, Civenni G, Losa M, Svinkina T, Bielski CM, Kryukov GV, Cascione L, Napoli S, Enchev RI, Mutch DG, Carney ME, Berchuck A, Winterhoff BJN, Broaddus RR, Schraml P, Moch H, Bertoni F, Catapano CV, Peter M, Carr SA, Garraway LA, Wild PJ, Theurillat J-PP. Opposing effects of cancer-type-specific SPOP mutants on BET protein degradation and sensitivity to BET inhibitors. Nat Med. 2017 Sep;23(9):1046–1054.

Published In

Nat Med

DOI

EISSN

1546-170X

Publication Date

September 2017

Volume

23

Issue

9

Start / End Page

1046 / 1054

Location

United States

Related Subject Headings

  • Ubiquitination
  • Triazoles
  • Transcription Factors
  • Reverse Transcriptase Polymerase Chain Reaction
  • Repressor Proteins
  • RNA-Binding Proteins
  • Protein Serine-Threonine Kinases
  • Prostatic Neoplasms
  • Nuclear Proteins
  • Neoplasms, Cystic, Mucinous, and Serous