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

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

doi:10.18632/oncotarget.2092

Eleftherios P Samartzis, Katrin Gutsche + Show 4 more

Open Access

https://doi.org/10.18632/oncotarget.2092

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Journal: Oncotarget	Publication Date: Jun 11, 2014
Citations: 147	License type: cc-by

Affiliation: University Hospital of Zurich

Abstract

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.

Highlights

Mutations in the gene encoding the AT-rich interacting domain containing protein 1A (ARID1A) are frequently observed in a wide variety of gynecological and non-gynecological cancers [1, 2]. These occur in approximately 50% of endometriosis-associated ovarian clear cell (OCCC) and 30% of endometrioid ovarian carcinomas (EnOC) [3, 4], in endometrial carcinomas, with a loss of expression in 20-30% depending on the histological subtype [5, 6], as well as in breast carcinomas [7, 8]
No significant difference in sensitivity to treatment with MK-2206 or perifosine was found in the ARID1A-deficient OCCC cell line OVSAYO after transfection with ARID1A siRNA
The results of this study demonstrate an interdependency of ARID1A and the PI3K/AKT pathway, which results in significantly increased sensitivity of ARID1A-deficient cancer cells to PI3Kand AKT- inhibition

Summary

Introduction

Mutations in the gene encoding the AT-rich interacting domain containing protein 1A (ARID1A) are frequently observed in a wide variety of gynecological and non-gynecological cancers [1, 2]. These occur in approximately 50% of endometriosis-associated ovarian clear cell (OCCC) and 30% of endometrioid ovarian carcinomas (EnOC) [3, 4], in endometrial carcinomas, with a loss of expression in 20-30% depending on the histological subtype [5, 6], as well as in breast carcinomas (mutations in 4-35%) [7, 8]. It has recently been shown in endometrial cancer that loss of ARID1A expression leads to an increased phosphorylation of AKT at Ser-473[21]

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