Potential therapeutic targets in ARID1A-mutated cancers Ovarian Cancer and Us OVARIAN CANCER and US Ovarian Cancer and Us

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Wednesday, July 01, 2015

Potential therapeutic targets in ARID1A-mutated cancers



abstract

 The Wistar Institute, Gene Expression and Regulation Program , Room 312, Philadelphia, PA 19104 , USA +1 215 495 6840 ; rzhang@wistar.org.

Abstract

ARID1A is a subunit of the Switch/Sucrose Non-Fermentable (SWI/SNF) chromatin-remodeling complex that regulates gene expression by controlling gene accessibility. ARID1A shows one of the highest mutation rates across different human cancer types. For example, ARID1A is mutated in ∼ 50% of ovarian clear cell carcinoma (OCCC). There is considerable interest in developing cancer therapeutics that correlate with ARID1A mutational status. A recent study demonstrated a synthetic lethality by targeting EZH2 histone methyltransferase activity in ARID1A-mutated OCCC using a clinically applicable small-molecule inhibitor. The observed synthetic lethality correlated with inhibition of PI3K/AKT signaling. In addition, there is evidence indicating that ARID1A-mutated cancer may also be subjected to therapeutic intervention by targeting residual SWI/SNF activity, the PI3K/AKT pathway, the DNA damage response, the tumor immunological microenvironment and stabilizing wild-type p53. In summary, we propose EZH2 inhibitor-based combinatorial strategies for targeting ARID1A-mutated cancers.

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