Loss of DAXX/ATRX Protein Expression Results in Ischemia Resistance and Radiation Sensitivity in Pancreatic Neuroendocrine Tumor Cells and Is Associated with Improved Response to Trans-Arterial Radioembolization

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INTRODUCTION: Metastatic liver pancreatic neuroendocrine tumors (PNETs) can be treated with ischemia-based trans-arterial embolization/trans-arterial chemo-embolization or radiation-based trans-arterial radioembolization (TARE). Guidelines for treatment selection are limited. The purpose of this study was to measure the effect of loss of DAXX/ATRX protein expression on ischemia and radiation sensitivity in Bon-1 and QGP-1 cells, and to compare TARE response in PNETs with and without a DAXX/ATRX mutation. METHODS: This was a laboratory investigation and retrospective review of an institutional database of TARE-treated PNET patients. Ischemia and radiation sensitivity were tested on Bon-1 and QGP-1 cells and CRISPR-generated DAXX (C16/C45) and ATRX (QAX12/QAX24) knockouts. Post-ischemia and postradiation cell viability, survival fraction, and caspase-3 expression were measured. Local progression-free survival (LPFS) was measured from time of TARE to local progression or death and estimated using Cox proportional hazards. RESULTS: Post-ischemia DAXX (C16/C45) and ATRX (QAX12/QAX24) knockouts had increased cell viability compared with Bon-1 wild-type cells (p < 0.0001, days 3, 5) and QGP-1 wild-type cells (p < 0.0001, days 3, 5, 7). Postradiation C16/C45 and QAX12/QAX24 had decreased survival fraction compared with respective wild type (p < 0.0001, all cell lines). C16/C45 had decreased apoptotic activity post-ischemia and increased apoptotic activity postradiation compared with wild type (p < 0.0001, all cell lines). Presence of DAXX/ATRX mutation was associated with longer LPFS after TARE (p < 0.001). Median LPFS after TARE was 6 months in wild type compared with 22 months in patients with DAXX/ATRX mutation. CONCLUSION: Loss of DAXX/ATRX protein expression is associated with ischemia resistance and radiation sensitivity in Bon-1 and QGP-1 cells and longer LPFS after TARE in PNET patients.

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