Loss of ARID1A in Tumor Cells Renders Selective Vulnerability to Combined Ionizing Radiation and PARP Inhibitor Therapy

Clin Cancer Res. 2019 Sep 15;25(18):5584-5594. doi: 10.1158/1078-0432.CCR-18-4222. Epub 2019 Jun 13.

Abstract

Purpose: Somatic inactivating mutations in ARID1A, a component of the SWI/SNF chromatin remodeling complex, are detected in various types of human malignancies. Loss of ARID1A compromises DNA damage repair. The induced DNA damage burden may increase reliance on PARP-dependent DNA repair of cancer cells to maintain genome integrity and render susceptibility to PARP inhibitor therapy.Experimental Design: Isogenic ARID1A-/- and wild-type cell lines were used for assessing DNA damage response, DNA compactness, and profiling global serine/threonine phosphoproteomic in vivo. A panel of inhibitors targeting DNA repair pathways was screened for a synergistic antitumor effect with irradiation in ARID1A-/- tumors.

Results: ARID1A-deficient endometrial cells exhibit sustained levels in DNA damage response, a result further supported by in vivo phosphoproteomic analysis. Our results show that ARID1A is essential for establishing an open chromatin state upon DNA damage, a process required for recruitment of 53BP1 and RIF1, key mediators of non-homologous end-joining (NHEJ) machinery, to DNA lesions. The inability of ARID1A-/- cells to mount NHEJ repair results in a partial cytotoxic response to radiation. Small-molecule compound screens revealed that PARP inhibitors act synergistically with radiation to potentiate cytotoxicity in ARID1A-/- cells. Combination treatment with low-dose radiation and olaparib greatly improved antitumor efficacy, resulting in long-term remission in mice bearing ARID1A-deficient tumors.

Conclusions: ARID1A-deficient cells acquire high sensitivity to PARP inhibition after exposure to exogenously induced DNA breaks such as ionizing radiation. Our findings suggest a novel biologically informed strategy for treating ARID1A-deficient malignancies.

Publication types

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

MeSH terms

  • Animals
  • Cell Cycle Proteins / metabolism
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • DNA Breaks, Double-Stranded
  • DNA Damage
  • DNA End-Joining Repair
  • DNA Repair
  • DNA-Binding Proteins / deficiency*
  • Disease Models, Animal
  • Drug Resistance, Neoplasm / genetics*
  • Gene Knockdown Techniques
  • Humans
  • Mice
  • Mice, Transgenic
  • Models, Biological
  • Poly(ADP-ribose) Polymerase Inhibitors / pharmacology*
  • Radiation Tolerance / genetics*
  • Transcription Factors / deficiency*

Substances

  • ARID1A protein, human
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Transcription Factors