Synapse - 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

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 Journal Article

Authors:	Puzzuoli, J. C.; Solivio, C.; Yuan, G.; Rizzo, A. J.; Graham, M. K.; Shenker, L.; Vista, W.; Gil, A.; Singh, H.; Alexander, E.; Gonzalez-Aguirre, A.; Latzman, J.; Petre, E. N.; Yarmohammadi, H.; Erinjeri, J. P.; Covey, A.; Chan, E.; Russell, J.; Bodei, L.; Raj, N.; Reidy-Lagunes, D.; Heaphy, C. M.; Ziv, E.
Article Title:	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
Abstract:	<p>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. (c) 2025 S. Karger AG, Basel</p>
Keywords:	survival; biomarker; brachytherapy; radiosensitivity; embolization; pancreatic neuroendocrine tumor; daxx; atrx; telomeres; prognosis
Journal Title:	Neuroendocrinology
Volume:	115
Issue:	9
ISSN:	0028-3835
Publisher:	S. Karger AG
Publication status:	Published
Date Published:	2025-09-01
Online Publication Date:	2025-07-24
Start Page:	730
End Page:	740
Language:	English
ACCESSION:	WOS:001564562300001
DOI:	10.1159/000547041
PROVIDER:	wos
PMCID:	PMC12421922
PUBMED:	40706576
Notes:	Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed and PDF -- MSK corresponding author is Etay Ziv --Source: Wos