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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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