ARID1A Deficiency Impairs the DNA Damage Checkpoint and Sensitizes Cells to PARP Inhibitors

Cancer Discov. 2015 Jul;5(7):752-67. doi: 10.1158/2159-8290.CD-14-0849. Epub 2015 Jun 11.

Abstract

ARID1A, SWI/SNF chromatin remodeling complex subunit, is a recently identified tumor suppressor that is mutated in a broad spectrum of human cancers. Thus, it is of fundamental clinical importance to understand its molecular functions and determine whether ARID1A deficiency can be exploited therapeutically. In this article, we report a key function of ARID1A in regulating the DNA damage checkpoint. ARID1A is recruited to DNA double-strand breaks (DSB) via its interaction with the upstream DNA damage checkpoint kinase ATR. At the molecular level, ARID1A facilitates efficient processing of DSB to single-strand ends and sustains DNA damage signaling. Importantly, ARID1A deficiency sensitizes cancer cells to PARP inhibitors in vitro and in vivo, providing a potential therapeutic strategy for patients with ARID1A-mutant tumors.

Significance: ARID1A has been identified as one of the most frequently mutated genes across human cancers. Our data suggest that clinical utility of PARP inhibitors might be extended beyond patients with BRCA mutations to a larger group of patients with ARID1A-mutant tumors, which may exhibit therapeutic vulnerability to PARP inhibitors.

Publication types

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

MeSH terms

  • Animals
  • Ataxia Telangiectasia Mutated Proteins / metabolism
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / genetics
  • Cell Line, Tumor
  • DNA Breaks, Double-Stranded
  • DNA Damage*
  • DNA-Binding Proteins
  • Female
  • HCT116 Cells
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / genetics
  • Male
  • Mice
  • Nuclear Proteins / chemistry
  • Nuclear Proteins / deficiency*
  • Poly(ADP-ribose) Polymerase Inhibitors / administration & dosage*
  • Poly(ADP-ribose) Polymerase Inhibitors / pharmacology
  • Transcription Factors / chemistry
  • Transcription Factors / deficiency*
  • Xenograft Model Antitumor Assays

Substances

  • ARID1A protein, human
  • DNA-Binding Proteins
  • Nuclear Proteins
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Transcription Factors
  • ATR protein, human
  • Ataxia Telangiectasia Mutated Proteins