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

Clinical Cancer Research Online First Ar.. by Park, Y., Chui, M. H., Suryo Rahman.. - 33m ago Preview

 
 
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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 repairs, and induced DNA damage burdens may increase the reliance on PARP-dependent DNA repairs of cancer cells to maintain genome integrity and renders cell 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 anti-tumor effect with irradiation in ARID1A-/- tumors. Results: ARID1A-deficient endometrial cells exhibited sustained levels in DNA damage response, a result further supported by in vivo phosphoproteomic analysis. Our results showed that ARID1A is 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 inhibitor acted synergistically with radiation to potentiate cytotoxicity in ARID1A-/- cells. Combination treatment with low-dose radiation and olaparib greatly 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.