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

Purpose: Somatic inactivating mutations in ARID1A, a component of the SWI/SNF chromatin remodelingcomplex, are detected in various types of human malignancies. Loss of ARID1Acompromises DNA damagerepairs, and induced DNA damageburdens may increase the reliance on PARP-dependent DNA repairs of cancer cells to maintain genome integrity and renders cell susceptibility to PARP inhibitortherapy. Experimental Design: Isogenic ARID1A-/- and wild-type cell lines were used for assessing DNA damageresponse, DNA compactness and profiling global serine/threonine phosphoproteomicin vivo. A panel of inhibitors targeting DNA repair pathways was screened for a synergistic anti-tumor effect with irradiation in ARID1A-/- tumors. Results: ARID1A-deficient endometrial cells exhibited sustained levels in DNA damageresponse, a result further supported by in vivo phosphoproteomicanalysis. Our results showed that ARID1Ais essential for establishing an open chromatin state upon DNA damages, a process that is 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 resulted in a partial cytotoxic response to radiation. Small-molecule compound screens indicated that PARP inhibitoracted synergistically with radiation to potentiate cytotoxicity in ARID1A-/- cells. Combination treatment with low-dose radiation and olaparibgreatly improved anti-tumor 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.