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Oncotarget. 2016 Jan 19;7(3):2545-54. doi: 10.18632/oncotarget.6309.

Concomitant BET and MAPK blockade for effective treatment of ovarian cancer.

Jing Y1, Zhang Z1,2, Ma P1, An S3,4, Shen Y3,4, Zhu L3,4, Zhuang G1,5.

Author information

1
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.
2
State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, RenJi Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
3
Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
4
Shanghai Collaborative Innovation Center for Translational Medicine, Shanghai, China.
5
Shanghai Key Laboratory of Gynecologic Oncology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.

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.

KEYWORDS:

BET inhibitors; MEK inhibitors; apoptosis; ovarian cancer; targeted therapy

PMID:
26575423
PMCID:
PMC4823054
DOI:
10.18632/oncotarget.6309
[Indexed for MEDLINE]
Free PMC Article

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