Potential therapeutic targets in ARID1A-mutated cancers

被引：59

作者：

Bitler, Benjamin G. ^{[1
]}

Fatkhutdinov, Nail ^{[1
,2
]}

Zhang, Rugang ^{[1
]}

机构：

[1] Wistar Inst Anat & Biol, Gene Express & Regulat Program, Room 312, Philadelphia, PA 19104 USA

[2] Kazan Fed Univ, Kazan, Russia

来源：

EXPERT OPINION ON THERAPEUTIC TARGETS | 2015年 / 19卷 / 11期

关键词：

ARID1A; EZH2; ovarian cancer; synthetic lethality; SWI/SNF COMPLEXES; SYNTHETIC LETHALITY; ARID1A; MUTATIONS; CARCINOMAS; EXPRESSION; CELLS;

D O I：

10.1517/14728222.2015.1062879

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

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.

引用

页码：1419 / 1422

页数：4

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