Intrinsic BET inhibitor resistance in SPOP-mutated prostate cancer is mediated by BET protein stabilization and AKT-mTORC1 activation.
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.
Mesh Terms:
Azepines, Blotting, Western, Cell Line, Tumor, Cell Proliferation, Cell Survival, Drug Resistance, Neoplasm, Gene Expression Profiling, Humans, Immunoprecipitation, Male, Mechanistic Target of Rapamycin Complex 1, Molecular Targeted Therapy, Multiprotein Complexes, Mutation, Nuclear Proteins, Prostatic Neoplasms, Proteasome Endopeptidase Complex, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins c-akt, RNA-Binding Proteins, Repressor Proteins, Reverse Transcriptase Polymerase Chain Reaction, TOR Serine-Threonine Kinases, Transcription Factors, Triazoles, rac1 GTP-Binding Protein
Azepines, Blotting, Western, Cell Line, Tumor, Cell Proliferation, Cell Survival, Drug Resistance, Neoplasm, Gene Expression Profiling, Humans, Immunoprecipitation, Male, Mechanistic Target of Rapamycin Complex 1, Molecular Targeted Therapy, Multiprotein Complexes, Mutation, Nuclear Proteins, Prostatic Neoplasms, Proteasome Endopeptidase Complex, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins c-akt, RNA-Binding Proteins, Repressor Proteins, Reverse Transcriptase Polymerase Chain Reaction, TOR Serine-Threonine Kinases, Transcription Factors, Triazoles, rac1 GTP-Binding Protein
Nat. Med.
Date: Sep. 01, 2017
PubMed ID: 28805822
View in: Pubmed Google Scholar
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