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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • 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

Published Date

  • September 2017

Published In

Volume / Issue

  • 23 / 9

Start / End Page

  • 1046 - 1054

PubMed ID

  • 28805821

Pubmed Central ID

  • 28805821

Electronic International Standard Serial Number (EISSN)

  • 1546-170X

Digital Object Identifier (DOI)

  • 10.1038/nm.4372

Language

  • eng

Conference Location

  • United States