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Nat Med. 2014 Mar;20(3):251-4. doi: 10.1038/nm.3480. Epub 2014 Feb 23.

ARID1B is a specific vulnerability in ARID1A-mutant cancers.

Author information

  • 11] 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].
  • 21] 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].
  • 31] 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.
  • 41] Broad Institute of Harvard and MIT, Boston, Massachusetts, USA. [2] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
  • 5Broad Institute of Harvard and MIT, Boston, Massachusetts, USA.
  • 61] 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.
  • 7Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
  • 8Department of Cardiac Surgery, University of Michigan, Ann Arbor, Michigan, USA.
  • 91] 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.

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.

PMID:
24562383
[PubMed - indexed for MEDLINE]
PMCID:
PMC3954704
Free PMC Article
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