title: Potential therapeutic targets in ARID1A-mutated cancers.
abstract: 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 ∼ 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.
authors.affiliation: a 1 The Wistar Institute, Gene Expression and Regulation Program , Room 312, Philadelphia, PA 19104, USA +1 215 495 6840 ; rzhang@wistar.org.
authors.forename: Benjamin G
authors.initials: BG
authors.lastname: Bitler
authors.affiliation: a 1 The Wistar Institute, Gene Expression and Regulation Program , Room 312, Philadelphia, PA 19104, USA +1 215 495 6840 ; rzhang@wistar.org.|b 2 Kazan Federal University , Kazan, Russia.
authors.forename: Nail
authors.initials: N
authors.lastname: Fatkhutdinov
authors.affiliation: a 1 The Wistar Institute, Gene Expression and Regulation Program , Room 312, Philadelphia, PA 19104, USA +1 215 495 6840 ; rzhang@wistar.org.
authors.forename: Rugang
authors.initials: R
authors.lastname: Zhang
mesh_terms: D004268:DNA-Binding Proteins; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D058990:Molecular Targeted Therapy; D009154:Mutation; D009369:Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D009687:Nuclear Proteins / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy; D014157:Transcription Factors / Q000235:genetics*; D059016:Tumor Microenvironment
chemical_list: C112476:ARID1A protein, human; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors
keywords: ARID1A; EZH2; ovarian cancer; synthetic lethality