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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Aminopyridines / pharmacology
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Apoptosis / drug effects
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Apoptosis / physiology
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Breast Neoplasms / enzymology
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Breast Neoplasms / metabolism
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Breast Neoplasms / pathology
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Breast Neoplasms / therapy
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DNA-Binding Proteins
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Female
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Gene Knockdown Techniques
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Heterocyclic Compounds, 3-Ring / pharmacology
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Humans
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MCF-7 Cells
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Morpholines / pharmacology
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Nuclear Proteins / biosynthesis
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Nuclear Proteins / deficiency*
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoinositide-3 Kinase Inhibitors*
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Phosphorylation
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Phosphorylcholine / analogs & derivatives
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Phosphorylcholine / pharmacology
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Protein Kinase Inhibitors / pharmacology*
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Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / metabolism
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RNA, Small Interfering / administration & dosage
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RNA, Small Interfering / genetics
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Ribosomal Protein S6 Kinases, 70-kDa / metabolism
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Signal Transduction
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Transcription Factors / biosynthesis
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Transcription Factors / deficiency*
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Transfection
Substances
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ARID1A protein, human
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Aminopyridines
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DNA-Binding Proteins
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Heterocyclic Compounds, 3-Ring
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MK 2206
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Morpholines
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NVP-BKM120
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Nuclear Proteins
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Phosphoinositide-3 Kinase Inhibitors
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Protein Kinase Inhibitors
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RNA, Small Interfering
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Transcription Factors
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Phosphorylcholine
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perifosine
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Proto-Oncogene Proteins c-akt
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Ribosomal Protein S6 Kinases, 70-kDa