ARID1B is a specific vulnerability in ARID1A-mutant cancers

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Animals
  • Cell Line
  • Cell Nucleus / metabolism
  • Cell Proliferation
  • Chromatin / metabolism
  • DNA-Binding Proteins / genetics*
  • False Positive Reactions
  • Fibroblasts / cytology
  • Fibroblasts / metabolism
  • Gene Expression Regulation, Neoplastic*
  • Gene Silencing
  • HEK293 Cells
  • Humans
  • Mice
  • Mutation*
  • Neoplasms / genetics*
  • Nuclear Proteins / genetics*
  • RNA, Small Interfering / metabolism
  • Time Factors
  • Transcription Factors / genetics*

Substances

  • ARID1A protein, human
  • ARID1B protein, human
  • Chromatin
  • DNA-Binding Proteins
  • Nuclear Proteins
  • RNA, Small Interfering
  • Transcription Factors