Opposing effects of cancer-type-specific SPOP mutants on BET protein degradation and sensitivity to BET inhibitors.
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.
Duke Scholars
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Related Subject Headings
- Ubiquitination
- Triazoles
- Transcription Factors
- Reverse Transcriptase Polymerase Chain Reaction
- Repressor Proteins
- RNA-Binding Proteins
- Protein Serine-Threonine Kinases
- Prostatic Neoplasms
- Nuclear Proteins
- Neoplasms, Cystic, Mucinous, and Serous
Citation
Published In
DOI
EISSN
Publication Date
Volume
Issue
Start / End Page
Location
Related Subject Headings
- Ubiquitination
- Triazoles
- Transcription Factors
- Reverse Transcriptase Polymerase Chain Reaction
- Repressor Proteins
- RNA-Binding Proteins
- Protein Serine-Threonine Kinases
- Prostatic Neoplasms
- Nuclear Proteins
- Neoplasms, Cystic, Mucinous, and Serous