American Association for Cancer Research
10780432ccr184222-sup-214345_2_supp_5551076_ps89zb.docx (6.05 MB)

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

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journal contribution
posted on 2023-03-31, 21:00 authored by 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

Supplementary Figures and Methods



Gray Foundation

Johns Hopkins University



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. 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. 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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