Journal Article

Intrinsic BET inhibitor resistance in SPOP-mutated prostate cancer is mediated by BET protein stabilization and AKT–mTORC1 activation

Pan, Chun-Wu, Zhao, Yu, Yang, Yinhui, Yan, Yuqian, Wang, Shangqian, Zhao, Shimin, Gao, Kun, Ye, Zhenqing, Wang, Chenji, Li, Yao, Wang, Liguo, Lin, Dong, Zhang, Pingzhao, Ren, Shancheng, Wang, Dejie, He, Yundong, Sun, Yinghao, Zhu, Yasheng, Chen, Yu, Wu, Di, Liu, Xiuping, Yu, Long, Lu, Daru, Wang, Yuzhuo, Huang, Haojie, Zhang, Jun

2017

Overview

Mutations in SPOP , the gene encoding a component of the E3 ubiquitin ligase complex, impair ubiquitination-dependent degradation of BRD2, BRD3 and BRD4 proteins and result in activation of ATK–mTORC1 signaling and resistance to BET inhibitors. Pharmacological blockade of AKT represents a viable strategy to restore the sensitivity of SPOP-mutant prostate tumors to BET inhibitors. These results, together with findings by Dai et al . and Janouskova et al ., uncover a new nongenetic mechanism of resistance to BET inhibition involving cancer-type-specific mutations in SPOP , and support the evaluation of SPOP mutation status to inform the administration of BET inhibitors in the clinic. 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 13/1 / 13/105 / 13/109 / 13/51 / 38/15 / 38/22 / 38/23 / 631/67/1059/602 / 631/80/458/582 / 631/80/474/2073 / 631/80/86 / 82/111 / 82/29 / 82/80 / AKT protein / Azepines - pharmacology / Azepines - therapeutic use / Bet protein / Binding / Biomarkers / Biomedicine / Biosynthesis / Blotting, Western / Cancer Research / 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 / Genetic aspects / Guanosine triphosphatases / Humans / Immunoprecipitation / Infectious Diseases / Inhibitor drugs / Inhibitors / letter / Male / Mechanistic Target of Rapamycin Complex 1 / Metabolic Diseases / Molecular Medicine / Molecular Targeted Therapy / Multiprotein Complexes - drug effects / Multiprotein Complexes - metabolism / Mutation / Neurosciences / 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