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

Hana Janouskova, Geniver El Tekle, Elisa Bellini, Namrata D. Udeshi, Anna Rinaldi, Anna Ulbricht, Tiziano Bernasocchi, Gianluca Civenni, Marco Losa, Tanya Svinkina, Craig M. Bielski, Gregory V. Kryukov, Luciano Cascione, Sara Napoli, Radoslav I. Enchev, David G. Mutch, Michael E. Carney, Andrew Berchuck, Boris J.N. Winterhoff, Russell R. BroaddusPeter Schraml, Holger Moch, Francesco Bertoni, Carlo V. Catapano, Matthias Peter, Steven A. Carr, Levi A. Garraway, Peter J. Wild, Jean Philippe P. Theurillat

Research output: Contribution to journalArticlepeer-review

95 Scopus citations

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.

Original languageEnglish
Pages (from-to)1046-1054
Number of pages9
JournalNature medicine
Volume23
Issue number9
DOIs
StatePublished - Sep 1 2017

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