Opposing effects of cancer-type-specific SPOP mutants on BET protein degradation and sensitivity to BET inhibitors
Authors listHana 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 Enchev David G Mutch Michael E Carney Andrew Berchuck Boris JN Winterhoff Russell R Broaddus Peter Schraml Holger Moch Francesco Bertoni Carlo V Catapano Matthias Peter Steven A Carr Levi A Garraway Peter J Wild Jean-Philippe P Theurillat
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.