Cancer Type-Specific SPOP Mutants Alter BET Protein Levels and Inhibitor Responses

It is generally assumed that recurrent mutations within a given cancer driver gene elicit similar drug responses. Recently, cancer genome studies have delineated recurrent but divergent missense mutations in the substrate recognition domain of the ubiquitin ligase adaptor SPOP in endometrial and prostate cancer. Their therapeutic implications remain incompletely understood. Here, we analyzed changes in the ubiquitin landscape induced by endometrial cancer-associated mutations of SPOP and identified altered ubiquitylation in a subset of proteins. Of these, bromodomain and extra-terminal (BET) proteins BRD2, BRD3, and BRD4 emerged as SPOP-CUL3 substrates that are increasingly recognized and degraded by endometrial type of SPOP mutants. The resulting reduction of BET protein levels sensitized cancer cells to BET inhibitors – an attractive class of anti-cancer therapeutics. Conversely, prostate cancer-specific mutants of SPOP impaired ubiquitylation and degradation of BET proteins promoting resistance against their pharmacologic inhibition. These results uncover a paradoxical aspect of oncogenomics, whereby mutations within the same domain of a particular gene evoke opposing drug susceptibilities. More specifically, we provide a molecular rational for the use of BET inhibitors to treat endometrial but not prostate cancer patients with SPOP mutations.