Prostate cancer-associated SPOP mutations confer resistance to BET inhibitors through stabilization of BRD4.
Xiangpeng Dai,Wenjian Gan,Xiaoning Li,Xiaoning Li,Shangqian Wang,Wei Zhang,Ling Huang,Shengwu Liu,Qing Zhong,Jianping Guo,Jinfang Zhang,Ting Chen,Kouhei Shimizu,Francisco Beca,Mirjam Blattner,Divya Vasudevan,Dennis L. Buckley,Jun Qi,Lorenz Buser,Pengda Liu,Hiroyuki Inuzuka,Andrew H. Beck,Liewei Wang,Peter J. Wild,Levi A. Garraway,Mark A. Rubin,Christopher E. Barbieri,Kwok-Kin Wong,Senthil K. Muthuswamy,Jiaoti Huang,Yu Chen,James E. Bradner,Wenyi Wei +32 more
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TLDR
The results elucidate the tumor-suppressor role of SPOP in prostate cancer in which it acts as a negative regulator of BET protein stability and also provide a molecular mechanism for resistance to BET inhibitors in individuals with prostate cancer bearing SPOP mutations.Abstract:
The bromodomain and extraterminal (BET) family of proteins comprises four members-BRD2, BRD3, BRD4 and the testis-specific isoform BRDT-that largely function as transcriptional coactivators and play critical roles in various cellular processes, including the cell cycle, apoptosis, migration and invasion. BET proteins enhance the oncogenic functions of major cancer drivers by elevating the expression of these drivers, such as c-Myc in leukemia, or by promoting the transcriptional activities of oncogenic factors, such as AR and ERG in prostate cancer. Pathologically, BET proteins are frequently overexpressed and are clinically linked to various types of human cancer; they are therefore being pursued as attractive therapeutic targets for selective inhibition in patients with cancer. To this end, a number of bromodomain inhibitors, including JQ1 and I-BET, have been developed and have shown promising outcomes in early clinical trials. Although resistance to BET inhibitors has been documented in preclinical models, the molecular mechanisms underlying acquired resistance are largely unknown. Here we report that cullin-3SPOP earmarks BET proteins, including BRD2, BRD3 and BRD4, for ubiquitination-mediated degradation. Pathologically, prostate cancer-associated SPOP mutants fail to interact with and promote the degradation of BET proteins, leading to their elevated abundance in SPOP-mutant prostate cancer. As a result, prostate cancer cell lines and organoids derived from individuals harboring SPOP mutations are more resistant to BET-inhibitor-induced cell growth arrest and apoptosis. Therefore, our results elucidate the tumor-suppressor role of SPOP in prostate cancer in which it acts as a negative regulator of BET protein stability and also provide a molecular mechanism for resistance to BET inhibitors in individuals with prostate cancer bearing SPOP mutations.read more
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Cyclin D–CDK4 kinase destabilizes PD-L1 via cullin 3–SPOP to control cancer immune surveillance
Jinfang Zhang,Xia Bu,Haizhen Wang,Yasheng Zhu,Yan Geng,Naoe Taira Nihira,Yuyong Tan,Yuyong Tan,Yanpeng Ci,Yanpeng Ci,Fei Wu,Fei Wu,Xiangpeng Dai,Jianping Guo,Yu Han Huang,Caoqi Fan,Caoqi Fan,Shancheng Ren,Yinghao Sun,Gordon J. Freeman,Piotr Sicinski,Wenyi Wei +21 more
TL;DR: It is shown that PD-L1 protein abundance is regulated by cyclin D–CDK4 and the cullin 3–SPOP E3 ligase via proteasome-mediated degradation, which reveals the potential for using combination treatment with CDK4/6 inhibitors and PD-1–PD-L 1 immune checkpoint blockade to enhance therapeutic efficacy for human cancers.
Journal ArticleDOI
Genetics and biology of prostate cancer.
TL;DR: Improved disease management will also benefit from artificial intelligence-based expert decision support systems for proper standard of care, prognostic determinant biomarkers to minimize overtreatment of localized disease, and new standards of care accelerated by next-generation adaptive clinical trials.
Journal ArticleDOI
Bromodomains: a new target class for drug development
TL;DR: The current state of BET inhibitor biology is reviewed, the next wave of bromodomain inhibitors with clinical potential in oncology and non-oncology indications are discussed, and the lessons learned from BET inhibitor programmes should affect efforts to develop drugs that target non-BET bRomodomains and other epigenetic readers.
Journal ArticleDOI
Cancer Mutations of the Tumor Suppressor SPOP Disrupt the Formation of Active, Phase-Separated Compartments.
Jill J. Bouchard,Joel H. Otero,Daniel C. Scott,Elzbieta Szulc,Erik W. Martin,Nafiseh Sabri,Daniele Granata,Melissa R. Marzahn,Kresten Lindorff-Larsen,Xavier Salvatella,Brenda A. Schulman,Tanja Mittag +11 more
TL;DR: It is shown that substrates trigger phase separation of SPOP in vitro and co-localization in membraneless organelles in cells and underlies the regulation of ubiquitin-dependent proteostasis.
Journal ArticleDOI
Reshaping the Tumor Stroma for Treatment of Pancreatic Cancer
Claire Vennin,Kendelle J. Murphy,Kendelle J. Murphy,Jennifer P. Morton,Thomas R. Cox,Thomas R. Cox,Marina Pajic,Marina Pajic,Paul Timpson,Paul Timpson +9 more
TL;DR: Relationships between the pancreatic tumor extracellular matrix, the vasculature, the immune system, and metabolism, are described and the implications for the development of stromal compartment-specific therapies are discussed.
References
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Selective inhibition of BET bromodomains.
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TL;DR: A cell-permeable small molecule (JQ1) that binds competitively to acetyl-lysine recognition motifs, or bromodomains is reported, establishing proof-of-concept for targeting protein–protein interactions of epigenetic ‘readers’, and providing a versatile chemical scaffold for the development of chemical probes more broadly throughout the b romodomain family.
Journal ArticleDOI
BET Bromodomain Inhibition as a Therapeutic Strategy to Target c-Myc
Jake Delmore,Ghayas C Issa,Madeleine E. Lemieux,Peter B. Rahl,Junwei Shi,Hannah M. Jacobs,Efstathios Kastritis,Timothy Gilpatrick,Ronald M. Paranal,Jun Qi,Marta Chesi,Anna C. Schinzel,Michael R. McKeown,Timothy P. Heffernan,Christopher R. Vakoc,P. Leif Bergsagel,Irene M. Ghobrial,Paul G. Richardson,Richard A. Young,William C. Hahn,William C. Hahn,Kenneth C. Anderson,Andrew L. Kung,James E. Bradner,Constantine S. Mitsiades +24 more
TL;DR: In this paper, a small-molecule bromodomain inhibitor, JQ1, was used to identify BET proteins as regulatory factors for c-Myc oncoprotein.
Journal ArticleDOI
Mechanisms of cancer drug resistance
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