Journal
EXPERT OPINION ON THERAPEUTIC TARGETS
Volume 19, Issue 11, Pages 1419-1422Publisher
TAYLOR & FRANCIS LTD
DOI: 10.1517/14728222.2015.1062879
Keywords
ARID1A; EZH2; ovarian cancer; synthetic lethality
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Funding
- NCI NIH HHS [R01 CA160331, CA010815, P30 CA010815, R01 CA163377, R01 CA202919] Funding Source: Medline
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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 similar to 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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