Journal Article

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

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

2017

Overview

Different mutations found in endometrial and prostate tumors affecting the substrate-recognition domain of SPOP, a component of the E3 ubiquitin ligase complex, result in opposing degradation activity of BET proteins and response to BET inhibitors. This work, along with findings by Zhang et al . and Dai et al ., highlights the divergent effects of recurrent mutations affecting different residues within the same functional domain of SPOP and provides scientific rationale to guide the administration of BET inhibitors in endometrial and prostate cancer patients harboring SPOP mutations. 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: Nature Publishing Group US,Nature Publishing Group
• Subject: 13 / 13/1 / 13/105 / 13/106 / 13/109 / 13/2 / 13/51 / 13/89 / 38 / 38/23 / 38/77 / 38/88 / 38/90 / 38/91 / 49/39 / 631/67/1059/602 / 631/67/68/2486 / 82/29 / 82/58 / Acetanilides - pharmacology / Adenocarcinoma, Clear Cell - genetics / Adenocarcinoma, Clear Cell - metabolism / Animals / Apoptosis - drug effects / Azepines - pharmacology / Bet protein / Biodegradation / Biomedicine / Cancer / Cancer Research / Carcinoma, Endometrioid - genetics / Carcinoma, Endometrioid - metabolism / Carcinosarcoma - genetics / Carcinosarcoma - metabolism / Care and treatment / Cell Cycle Proteins / Cell Line, Tumor / Cell Proliferation - drug effects / Chromatography, Liquid / Cullin Proteins - metabolism / Degradation / Drug Resistance, Neoplasm / Endometrial cancer / Endometrial Neoplasms - genetics / Endometrial Neoplasms - metabolism / Endometrium / Epigenesis, Genetic / Female / Gene mapping / Gene mutation / Genetic aspects / Heterocyclic Compounds, 3-Ring - pharmacology / Humans / Immunoblotting / Immunohistochemistry / Immunoprecipitation / Infectious Diseases / Inhibitor drugs / Inhibitors / Male / Mass Spectrometry / Metabolic Diseases / Mice, Nude / Missense mutation / Molecular Medicine / Molecular Targeted Therapy / Mutation / Neoplasm Transplantation / Neoplasms, Cystic, Mucinous, and Serous - genetics / Neoplasms, Cystic, Mucinous, and Serous - metabolism / Neurosciences / Nuclear Proteins - antagonists & inhibitors / Nuclear Proteins - genetics / Nuclear Proteins - metabolism / Pharmacology / Physiological aspects / Prostate cancer / Prostatic Neoplasms - genetics / Prostatic Neoplasms - metabolism / Protein Serine-Threonine Kinases - antagonists & inhibitors / Protein Serine-Threonine Kinases - metabolism / Proteins / Proteolysis / Repressor Proteins - genetics / Reverse Transcriptase Polymerase Chain Reaction / RNA-Binding Proteins - antagonists & inhibitors / RNA-Binding Proteins - metabolism / Sensitivity / Substrates / Transcription Factors - antagonists & inhibitors / Transcription Factors - metabolism / Triazoles - pharmacology / Ubiquitin / Ubiquitin-protein ligase / Ubiquitination