title: Concomitant BET and MAPK blockade for effective treatment of ovarian cancer.
abstract: Ovarian cancer is the most lethal gynecologic malignancy, and it is imperative to develop new treatments to ameliorate patient survival. Using an anti-cancer drug library containing 180 small molecule inhibitors, we performed a high-content image-based screen and found that BET and MEK inhibitors are among the candidates which were able to effectively inhibit ovarian cancer cell growth. However, BET inhibition alone was largely cytostatic, possibly due to feedback activation of the MAPK pathway. Consequently, the combination of MEK and BET inhibitors suppressed both cell proliferation and survival, and was more efficacious than single agent. Mechanistically, BET and MEK inhibitors exerted synergistic effects on apoptosis regulators including BIM and BAD. Our findings support concomitant BET and MAPK blockade as an effective therapeutic strategy in ovarian cancer.
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, RenJi Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Jing
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, RenJi Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.|State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, RenJi Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Zhenfeng
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, RenJi Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Pengfei
authors.initials: P
authors.lastname: Ma
authors.affiliation: Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.|Shanghai Collaborative Innovation Center for Translational Medicine, Shanghai, China.
authors.forename: Shimin
authors.initials: S
authors.lastname: An
authors.affiliation: Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.|Shanghai Collaborative Innovation Center for Translational Medicine, Shanghai, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.|Shanghai Collaborative Innovation Center for Translational Medicine, Shanghai, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Zhu
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, RenJi Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.|Shanghai Key Laboratory of Gynecologic Oncology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Guanglei
authors.initials: G
authors.lastname: Zhuang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D057166:High-Throughput Screening Assays / Q000379:methods; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D054852:Small Molecule Libraries / Q000494:pharmacology*; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D000092468:Bromodomain Containing Proteins
chemical_list: D018797:Cell Cycle Proteins; D020928:Mitogen-Activated Protein Kinases; D009687:Nuclear Proteins; D012333:RNA, Messenger; D054852:Small Molecule Libraries; D014157:Transcription Factors; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins
keywords: BET inhibitors; MEK inhibitors; apoptosis; ovarian cancer; targeted therapy