3 years ago

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

Opposing effects of cancer-type-specific SPOP mutants on BET protein degradation and sensitivity to BET inhibitors
Elisa Bellini, Steven A Carr, Holger Moch, Luciano Cascione, Gregory V Kryukov, Francesco Bertoni, Michael E Carney, Matthias Peter, Boris J N Winterhoff, David G Mutch, Sara Napoli, Marco Losa, Namrata D Udeshi, Radoslav I Enchev, Tanya Svinkina, Peter Schraml, Tiziano Bernasocchi, Peter J Wild, Jean-Philippe P Theurillat, Carlo V Catapano, Craig M Bielski, Anna Rinaldi, Andrew Berchuck, Hana Janouskova, Geniver El Tekle, Russell R Broaddus, Levi A Garraway, Gianluca Civenni, Anna Ulbricht
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.

Publisher URL: http://dx.doi.org/10.1038/nm.4372

DOI: 10.1038/nm.4372

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