Loss of ARID1A in tumor cells renders selective vulnerability to combined ionizing radiation and PARP inhibitor therapy

Youngran Park, M. Herman Chui, Yohan Suryo Rahmanto, Zheng Cheng Yu, Raghavendra A. Shamanna, Marina A. Bellani, Stephanie Gaillard, Ayse Ayhan, Akila Viswanathan, Michael M. Seidman, Sonia Franco, Anthony K.L. Leung, Vilhelm A. Bohr, Ie Ming Shih, Tian Li Wang

Research output: Contribution to journalArticlepeer-review

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 nonhomologous 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 ARID1Adeficient 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 ARID1Adeficient malignancies.

Original languageEnglish (US)
Pages (from-to)5584-5593
Number of pages10
JournalClinical Cancer Research
Volume25
Issue number18
DOIs
StatePublished - Sep 15 2019

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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