4.3 Article

Concomitant BET and MAPK blockade for effective treatment of ovarian cancer

Journal

ONCOTARGET
Volume 7, Issue 3, Pages 2545-2554

Publisher

IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.6309

Keywords

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

Funding

  1. National Natural Science Foundation of China [81472537, 81502597]
  2. State Key Laboratory of Oncogenes and Related Genes [91-14-18, 91-15-12]
  3. Shanghai Institutions of Higher Learning (Eastern Scholar)

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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.

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