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

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

Author information

1
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
2
Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
3
Laboratory of Molecular Gerontology, National Institute on Aging, NIH, Baltimore, Maryland.
4
Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
5
Department of Gynecology/Obstetrics, Johns Hopkins University School of Medicine, Baltimore, Maryland.
6
Department of Pathology, Seirei Mikatahara General Hospital, Hamamatsu, Japan.
7
Hiroshima University School of Medicine, Hiroshima, Japan.
8
Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland.
9
Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland.
10
Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. ishih@jhmi.edu tlw@jhmi.edu.
11
Richard W. TeLinde Gynecologic Pathology Research Program, Johns Hopkins University School of Medicine, Baltimore, Maryland.
12
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland. ishih@jhmi.edu tlw@jhmi.edu.

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.

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