title: ARID1B is a specific vulnerability in ARID1A-mutant cancers.
abstract: Recent studies have revealed that ARID1A, encoding AT-rich interactive domain 1A (SWI-like), is frequently mutated across a variety of human cancers and also has bona fide tumor suppressor properties. Consequently, identification of vulnerabilities conferred by ARID1A mutation would have major relevance for human cancer. Here, using a broad screening approach, we identify ARID1B, an ARID1A homolog whose gene product is mutually exclusive with ARID1A in SWI/SNF complexes, as the number 1 gene preferentially required for the survival of ARID1A-mutant cancer cell lines. We show that loss of ARID1B in ARID1A-deficient backgrounds destabilizes SWI/SNF and impairs proliferation in both cancer cells and primary cells. We also find that ARID1A and ARID1B are frequently co-mutated in cancer but that ARID1A-deficient cancers retain at least one functional ARID1B allele. These results suggest that loss of ARID1A and ARID1B alleles cooperatively promotes cancer formation but also results in a unique functional dependence. The results further identify ARID1B as a potential therapeutic target for ARID1A-mutant cancers.
authors.affiliation: 1] Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [2] Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts, USA. [3] Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA. [4] Biological and Biomedical Sciences Program, Harvard Medical School, Boston, Massachusetts, USA. [5].
authors.forename: Katherine C
authors.initials: KC
authors.lastname: Helming
authors.affiliation: 1] Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [2] Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts, USA. [3] Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA. [4].
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Wang
authors.affiliation: 1] Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [2] Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts, USA. [3] Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Boris G
authors.initials: BG
authors.lastname: Wilson
authors.affiliation: 1] Broad Institute of Harvard and MIT, Boston, Massachusetts, USA. [2] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Francisca
authors.initials: F
authors.lastname: Vazquez
authors.affiliation: 1] Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [2] Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts, USA. [3] Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Haswell
authors.affiliation: 1] Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [2] Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts, USA. [3] Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Haley E
authors.initials: HE
authors.lastname: Manchester
authors.affiliation: 1] Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [2] Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts, USA. [3] Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Youngha
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Broad Institute of Harvard and MIT, Boston, Massachusetts, USA.
authors.forename: Gregory V
authors.initials: GV
authors.lastname: Kryukov
authors.affiliation: Broad Institute of Harvard and MIT, Boston, Massachusetts, USA.
authors.forename: Mahmoud
authors.identifier: 0000000318972265
authors.initials: M
authors.lastname: Ghandi
authors.affiliation: 1] Broad Institute of Harvard and MIT, Boston, Massachusetts, USA. [2] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [3] Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Aguirre
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Zainab
authors.initials: Z
authors.lastname: Jagani
authors.affiliation: Department of Cardiac Surgery, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Wang
authors.affiliation: 1] Broad Institute of Harvard and MIT, Boston, Massachusetts, USA. [2] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [3] Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Levi A
authors.initials: LA
authors.lastname: Garraway
authors.affiliation: 1] Broad Institute of Harvard and MIT, Boston, Massachusetts, USA. [2] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [3] Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: William C
authors.initials: WC
authors.lastname: Hahn
authors.affiliation: 1] Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [2] Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts, USA. [3] Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA. [4] Broad Institute of Harvard and MIT, Boston, Massachusetts, USA. [5] Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Charles W M
authors.initials: CW
authors.lastname: Roberts
mesh_terms: D000483:Alleles; D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D002843:Chromatin / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics*; D005189:False Positive Reactions; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D009154:Mutation; D009369:Neoplasms / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D034741:RNA, Small Interfering / Q000378:metabolism; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics*
chemical_list: C112476:ARID1A protein, human; C497837:ARID1B protein, human; D002843:Chromatin; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D014157:Transcription Factors