Research Papers:

Loss of ARID1A expression sensitizes cancer cells to PI3K- and AKT-inhibition

Eleftherios P. Samartzis, Katrin Gutsche, Konstantin J. Dedes, Daniel Fink, Manuel Stucki and Patrick Imesch _

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Oncotarget. 2014; 5:5295-5303. https://doi.org/10.18632/oncotarget.2092

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Eleftherios P. Samartzis1, Katrin Gutsche1, Konstantin J. Dedes1, Daniel Fink1, Manuel Stucki1 and Patrick Imesch1

1 Department of Gynecology, University Hospital of Zurich, Zürich, Switzerland


Patrick Imesch, email:

Keywords: ARID1A; BAF250a; SWI/SNF; PI3K/AKT pathway; AKT phosphorylation; PIK3CA; apoptosis; AKT-inhibitor; MK-2206; perifosine; PI3K-inhibitor; buparlisib (BKM120); ovarian clear cell carcinomas; endometriosis associated ovarian carcinomas; endometrial cancer; breast cancer

Received: March 15, 2014 Accepted: June 11, 2014 Published: June 11, 2014


ARID1A mutations are observed in various tumors, including ovarian clear cell (OCCC) and endometrioid carcinomas, endometrial, and breast carcinomas. They commonly result in loss of ARID1A-protein expression and frequently co-occur with PI3K/AKT-pathway activating mechanisms. The aim of this study was to test the hypothesis as to whether PI3K/AKT-pathway activation is a critical mechanism in ARID1A-mutated tumors and if consequently ARID1A-deficient tumors show increased sensitivity to treatment with PI3K- and AKT-inhibitors. Upon ARID1A knockdown, MCF7 breast cancer cells and primary MRC5 cells exhibited a significantly increased sensitivity towards the AKT-inhibitors MK-2206 and perifosine, as well as the PI3K-inhibitor buparlisib. Knockdown of ARID1A in MCF7 led to an increase of pAKT-Ser473. AKT-inhibition with MK-2206 led to increased apoptosis and to a decrease of pS6K in ARID1A-depleted MCF7 cells but not in the controls. In five OCCC cell lines ARID1A-deficiency correlated with increased pAKT-Ser473 levels and with sensitivity towards treatment with the AKT-inhibitor MK-2206. In conclusion, ARID1A-deficient cancer cells demonstrate an increased sensitivity to treatment with small molecule inhibitors of the PI3K/AKT-pathway. These findings suggest a specific requirement of the PI3K/AKT pathway in ARID1A-deficient tumors and reveal a synthetic lethal interaction between loss of ARID1A expression and inhibition of the PI3K/AKT pathway.

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