title: Loss of ARID1A expression sensitizes cancer cells to PI3K- and AKT-inhibition.
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.
authors: Department of Gynecology, University Hospital of Zurich, Zürich, Switzerland.
authors: Eleftherios P
authors: EP
authors: Samartzis
authors: Department of Gynecology, University Hospital of Zurich, Zürich, Switzerland.
authors: Katrin
authors: K
authors: Gutsche
authors: Department of Gynecology, University Hospital of Zurich, Zürich, Switzerland.
authors: Konstantin J
authors: KJ
authors: Dedes
authors: Department of Gynecology, University Hospital of Zurich, Zürich, Switzerland.
authors: Daniel
authors: D
authors: Fink
authors: Department of Gynecology, University Hospital of Zurich, Zürich, Switzerland.
authors: Manuel
authors: M
authors: Stucki
authors: Department of Gynecology, University Hospital of Zurich, Zürich, Switzerland.
authors: Patrick
authors: P
authors: Imesch
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001943:Breast Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D004268:DNA-Binding Proteins; D005260:Female; D055785:Gene Knockdown Techniques; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D006801:Humans; D061986:MCF-7 Cells; D009025:Morpholines / Q000494:pharmacology; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D010767:Phosphorylcholine / Q000031:analogs & derivatives / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D014162:Transfection
chemical_list: D000631:Aminopyridines; D004268:DNA-Binding Proteins; D006575:Heterocyclic Compounds, 3-Ring; D009025:Morpholines; D009687:Nuclear Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010767:Phosphorylcholine; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D014157:Transcription Factors; C112476:ARID1A protein, human; C548887:MK 2206; C571178:NVP-BKM120; C105905:perifosine