title: Synthetic lethality by targeting EZH2 methyltransferase activity in ARID1A-mutated cancers.
abstract: The gene encoding ARID1A, a chromatin remodeler, shows one of the highest mutation rates across many cancer types. Notably, ARID1A is mutated in over 50% of ovarian clear cell carcinomas, which currently have no effective therapy. To date, clinically applicable targeted cancer therapy based on ARID1A mutational status has not been described. Here we show that inhibition of the EZH2 methyltransferase acts in a synthetic lethal manner in ARID1A-mutated ovarian cancer cells and that ARID1A mutational status correlated with response to the EZH2 inhibitor. We identified PIK3IP1 as a direct target of ARID1A and EZH2 that is upregulated by EZH2 inhibition and contributed to the observed synthetic lethality by inhibiting PI3K-AKT signaling. Importantly, EZH2 inhibition caused regression of ARID1A-mutated ovarian tumors in vivo. To our knowledge, this is the first data set to demonstrate a synthetic lethality between ARID1A mutation and EZH2 inhibition. Our data indicate that pharmacological inhibition of EZH2 represents a novel treatment strategy for cancers involving ARID1A mutations.
authors: Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, Pennsylvania, USA.
authors: Benjamin G
authors: BG
authors: Bitler
authors: Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, Pennsylvania, USA.
authors: Katherine M
authors: KM
authors: Aird
authors: Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, Pennsylvania, USA.
authors: Azat
authors: A
authors: Garipov
authors: Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, Pennsylvania, USA.
authors: Hua
authors: H
authors: Li
authors: Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, Pennsylvania, USA.
authors: Michael
authors: M
authors: Amatangelo
authors: Center for Systems and Computational Biology, The Wistar Institute, Philadelphia, Pennsylvania, USA.
authors: Andrew V
authors: AV
authors: Kossenkov
authors: Center for Chemical Biology and Translational Medicine, The Wistar Institute, Philadelphia, Pennsylvania, USA.
authors: David C
authors: DC
authors: Schultz
authors: Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, Pennsylvania, USA.
authors: Qin
authors: Q
authors: Liu
authors: Department of Pathology, Oncology, and Gynecology and Obstetrics, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA.
authors: Ie-Ming
authors: IeM
authors: Shih
authors: Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania, USA.
authors: Jose R
authors: JR
authors: Conejo-Garcia
authors: 1] Center for Systems and Computational Biology, The Wistar Institute, Philadelphia, Pennsylvania, USA. [2] Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, Pennsylvania, USA.
authors: David W
authors: DW
authors: Speicher
authors: Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, Pennsylvania, USA.
authors: Rugang
authors: R
authors: Zhang
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins; D000071221:Enhancer of Zeste Homolog 2 Protein; D005260:Female; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000378:metabolism*; D008780:Methyltransferases / Q000037:antagonists & inhibitors*; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D009687:Nuclear Proteins / Q000187:drug effects / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000235:genetics*; D063151:Polycomb Repressive Complex 2 / Q000037:antagonists & inhibitors*; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects / Q000378:metabolism*; D011728:Pyridones / Q000494:pharmacology*; D015398:Signal Transduction; D014157:Transcription Factors / Q000187:drug effects / Q000235:genetics*; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
chemical_list: C112476:ARID1A protein, human; D004268:DNA-Binding Proteins; C577920:GSK-2816126; D007211:Indoles; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009687:Nuclear Proteins; C521076:PIK3IP1 protein, human; D011728:Pyridones; D014157:Transcription Factors; D008780:Methyltransferases; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; D051057:Proto-Oncogene Proteins c-akt