ALT neuroblastoma chemoresistance due to telomere dysfunction-induced ATM activation is reversible with ATM inhibitor AZD0156

Cancers overcome replicative immortality by activating either telomerase or an alternative lengthening of telomeres (ALT) mechanism. ALT occurs in ~25% of high-risk neuroblastomas, and progression in patients with ALT neuroblastoma during or after front-line therapy is frequent and often fatal. Temo...

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Vydáno v:Science translational medicine Ročník 13; číslo 607
Hlavní autoři: Koneru, Balakrishna, Farooqi, Ahsan, Nguyen, Thinh H, Chen, Wan Hsi, Hindle, Ashly, Eslinger, Cody, Makena, Monish Ram, Burrow, Trevor A, Wilson, Joanne, Smith, Aaron, Pilla Reddy, Venkatesh, Cadogan, Elaine, Durant, Stephen T, Reynolds, C Patrick
Médium: Journal Article
Jazyk:angličtina
Vydáno: United States 18.08.2021
Témata:
Animals
Ataxia Telangiectasia
Ataxia Telangiectasia Mutated Proteins
Drug Resistance, Neoplasm
Humans
Mice
Neoplasm Recurrence, Local
Neuroblastoma - drug therapy
Pyridines
Quinolines
Telomere
Telomere Homeostasis
ISSN:1946-6242, 1946-6242
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Shrnutí:Cancers overcome replicative immortality by activating either telomerase or an alternative lengthening of telomeres (ALT) mechanism. ALT occurs in ~25% of high-risk neuroblastomas, and progression in patients with ALT neuroblastoma during or after front-line therapy is frequent and often fatal. Temozolomide + irinotecan is commonly used as salvage therapy for neuroblastoma. Patient-derived cell lines and xenografts established from patients with relapsed ALT neuroblastoma demonstrated de novo resistance to temozolomide + irinotecan [SN-38 in vitro, < 0.05; in vivo mouse event-free survival (EFS), < 0.0001] vs. telomerase-positive neuroblastomas. We observed that ALT neuroblastoma cells manifested constitutive ataxia-telangiectasia mutated (ATM) activation due to spontaneous telomere dysfunction which was not observed in telomerase-positive neuroblastoma cells. We demonstrated that induction of telomere dysfunction resulted in ATM activation that, in turn, conferred resistance to temozolomide + SN-38 (4.2-fold change in IC , < 0.001). ATM knockdown (shRNA) or inhibition using a clinical-stage small-molecule inhibitor (AZD0156) reversed resistance to temozolomide + irinotecan in ALT neuroblastoma cell lines in vitro ( < 0.001) and in four ALT xenografts in vivo (EFS, < 0.0001). AZD0156 showed modest to no enhancement of temozolomide + irinotecan activity in telomerase-positive neuroblastoma cell lines and xenografts. Ataxia telangiectasia and Rad3 related (ATR) inhibition using AZD6738 did not enhance temozolomide + SN-38 activity in ALT neuroblastoma cells. Thus, ALT neuroblastoma chemotherapy resistance occurs via ATM activation and is reversible with ATM inhibitor AZD0156. Combining AZD0156 with temozolomide + irinotecan warrants clinical testing for neuroblastoma.
Bibliografie:ObjectType-Article-1
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ISSN:1946-6242
1946-6242
DOI:10.1126/scitranslmed.abd5750