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

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 À/À 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 À/À 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 À/À 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 À/À 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.

Paradoxical role of AT-rich interactive domain 1A in restraining pancreatic carcinogenesis

“…Eventually, through loss of p53, or upregulation of oncogenic networks like Myc or stem cell transcription factors, a subset of Arid1a-depleted precursor cells progress to frank adenocarcinomas. Our data reassesses the utility of therapeutic vulnerabilities previously described in other ARID1A mutant cancer models (e.g., DNA repair defects or microsatellite instability), in the setting of PDAC 24,25,55 , while describing novel opportunities for targeting this class of cancers in the clinic.…”

“…Specifically, Arid1a localizes to sites of DSBs through its interaction with DNA repair checkpoints, with loss of Arid1a leading to compromised homologous recombination repair (HR) and non-homologous end joining (NHEJ), the two major arms of DSB repair. Further, these studies have also shown increased sensitivity of cell lines with ARID1A mutations to DSB inducing agents like cisplatin, radiation and to PARP inhibitors 24,25 . Surprisingly, our "KAC" cells were both relatively resistant to Cisplatin and PARP inhibitors (compared to the "KC" and "KPC" lines), and by the Comet assay, their DNA repair proficiency was comparable to these Arid1a wild type PDAC lines.…”

“…What mechanism underlies the inability of Arid1a-deleted precursor lesions to robustly proliferate in vivo? Parsing the GSEA data on the "KAC" PDAC lines identified DNA repair as one of the highly ranked pathways, which was paradoxical, since numerous prior studies in preclinical models have suggested that the ARID1A protein (and other members of the BAF complex) is integral to repair of DNA DSBs [24][25][26]55 . Specifically, Arid1a localizes to sites of DSBs through its interaction with DNA repair checkpoints, with loss of Arid1a leading to compromised homologous recombination repair (HR) and non-homologous end joining (NHEJ), the two major arms of DSB repair.…”

“…In light of our observations above, it is imperative that putative targets be distinguished into those that persist in the established PDAC, versus those that are present in precursor lesions, but are circumvented in established PDAC because of "escape" from Arid1a loss-induced growth constraints. For example, we posit that "escape" mechanisms are the basis for our observation that synthetic lethal effects described in other ARID1A mutant solid cancer models, such as susceptibility to PARP inhibition and cisplatin 24,25,55 , or to commercially available EZH2 inhibitors [61][62][63] , are absent in the autochthonous PDAC lines that have arisen in the setting of "escape". On the contrary, a striking "synthetic essentiality" 12 that is ubiquitously identified in the Arid1a mutant PDAC cells is the requirement of sustained ARID1B expression for survival.…”

“…Reports in various solid cancers have shown that ARID1A mutations in cell lines are associated with compromised DNA damage repair, and enhanced sensitivity to agents inducing DNA double strand break (DSB), such as Cisplatin, or to the recently developed class of PARP inhibitors 24,25 .…”