Janouskova H El Tekle G Bellini E Udeshi ND Rinaldi A Ulbricht A Bernasocchi T Civenni G Losa M Svinkina T Bielski CM Kryukov GV Cascione L Napoli S Enchev RI Mutch DG Carney ME Berchuck A Winterhoff BJN Broaddus RR Schraml P Moch H Bertoni F Catapano CV Peter M Carr SA Garraway LA Wild PJ Theurillat JP 2017 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. application/pdf https://sonar.ch/global/documents/199413 eng info:eu-repo/semantics/altIdentifier/doi/10.1038/nm.4372 info:eu-repo/semantics/altIdentifier/pmid/28805821 info:eu-repo/semantics/openAccess Nature medicine. - 2017 Acetanilides Adenocarcinoma, Clear Cell Animals Apoptosis Azepines Carcinoma, Endometrioid Carcinosarcoma Cell Cycle Proteins Cell Line, Tumor Cell Proliferation Chromatography, Liquid Cullin Proteins Drug Resistance, Neoplasm Endometrial Neoplasms Epigenesis, Genetic Female Heterocyclic Compounds, 3-Ring Humans Immunoblotting Immunohistochemistry Immunoprecipitation Male Mass Spectrometry Mice, Nude Molecular Targeted Therapy Mutation Neoplasm Transplantation Neoplasms, Cystic, Mucinous, and Serous Nuclear Proteins Prostatic Neoplasms Protein-Serine-Threonine Kinases RNA-Binding Proteins Repressor Proteins Reverse Transcriptase Polymerase Chain Reaction Transcription Factors Triazoles Ubiquitination Opposing effects of cancer-type-specific SPOP mutants on BET protein degradation and sensitivity to BET inhibitors. http://purl.org/coar/resource_type/c_6501