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Intrinsic BET inhibitor resistance in SPOP-mutated prostate cancer is mediated by BET protein stabilization and AKT-mTORC1 activation
Nature medicine, 2017-09, Vol.23 (9), p.1055-1062
2017

Details

Autor(en) / Beteiligte
Titel
Intrinsic BET inhibitor resistance in SPOP-mutated prostate cancer is mediated by BET protein stabilization and AKT-mTORC1 activation
Ist Teil von
  • Nature medicine, 2017-09, Vol.23 (9), p.1055-1062
Ort / Verlag
United States: Nature Publishing Group
Erscheinungsjahr
2017
Link zum Volltext
Beschreibungen/Notizen
  • Bromodomain and extraterminal domain (BET) protein inhibitors are emerging as promising anticancer therapies. The gene encoding the E3 ubiquitin ligase substrate-binding adaptor speckle-type POZ protein (SPOP) is the most frequently mutated in primary prostate cancer. Here we demonstrate that wild-type SPOP binds to and induces ubiquitination and proteasomal degradation of BET proteins (BRD2, BRD3 and BRD4) by recognizing a degron motif common among them. In contrast, prostate cancer-associated SPOP mutants show impaired binding to BET proteins, resulting in decreased proteasomal degradation and accumulation of these proteins in prostate cancer cell lines and patient specimens and causing resistance to BET inhibitors. Transcriptome and BRD4 cistrome analyses reveal enhanced expression of the GTPase RAC1 and cholesterol-biosynthesis-associated genes together with activation of AKT-mTORC1 signaling as a consequence of BRD4 stabilization. Our data show that resistance to BET inhibitors in SPOP-mutant prostate cancer can be overcome by combination with AKT inhibitors and further support the evaluation of SPOP mutations as biomarkers to guide BET-inhibitor-oriented therapy in patients with prostate cancer.
Sprache
Englisch
Identifikatoren
ISSN: 1078-8956
eISSN: 1546-170X
DOI: 10.1038/nm.4379
Titel-ID: cdi_pubmed_primary_28805822
Format
–
Schlagworte
AKT protein, Azepines - pharmacology, Azepines - therapeutic use, Bet protein, Binding, Biomarkers, Biosynthesis, Blotting, Western, Cancer, Cell Line, Tumor, Cell Proliferation - drug effects, Cell Survival, Cholesterol, Degradation, Drug resistance, Drug Resistance, Neoplasm, Drug therapy, Gene expression, Gene Expression Profiling, Gene mutation, Gene mutations, Genetic aspects, Guanosine triphosphatases, Humans, Immunoprecipitation, Inhibitor drugs, Inhibitors, Male, Mechanistic Target of Rapamycin Complex 1, Molecular Targeted Therapy, Multiprotein Complexes - drug effects, Multiprotein Complexes - metabolism, Mutants, Mutation, Nuclear Proteins - antagonists & inhibitors, Nuclear Proteins - drug effects, Nuclear Proteins - genetics, Nuclear Proteins - metabolism, Physiological aspects, Prostate cancer, Prostatic Neoplasms - drug therapy, Prostatic Neoplasms - genetics, Prostatic Neoplasms - metabolism, Proteasome Endopeptidase Complex - drug effects, Proteasomes, Protein-Serine-Threonine Kinases - antagonists & inhibitors, Protein-Serine-Threonine Kinases - drug effects, Protein-Serine-Threonine Kinases - metabolism, Proteins, Proto-Oncogene Proteins c-akt - drug effects, Proto-Oncogene Proteins c-akt - metabolism, rac1 GTP-Binding Protein - genetics, rac1 GTP-Binding Protein - metabolism, Rac1 protein, Repressor Proteins - genetics, Repressor Proteins - metabolism, Reverse Transcriptase Polymerase Chain Reaction, RNA-Binding Proteins - antagonists & inhibitors, RNA-Binding Proteins - drug effects, RNA-Binding Proteins - metabolism, Stabilization, TOR Serine-Threonine Kinases - drug effects, TOR Serine-Threonine Kinases - metabolism, Transcription activation, Transcription Factors - antagonists & inhibitors, Transcription Factors - drug effects, Transcription Factors - metabolism, Triazoles - pharmacology, Triazoles - therapeutic use, Tumor cell lines, Ubiquitin, Ubiquitin-protein ligase, Ubiquitination

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