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p53 Loss in MYC-Driven Neuroblastoma Leads to Metabolic Adaptations Supporting Radioresistance.

Yogev, Orli, Barker, Karen, Sikka, Arti, Almeida, Gilberto S, Hallsworth, Albert, Smith, Laura M, Jamin, Yann, Ruddle, Ruth, Koers, Alexander, Webber, Hannah T, Raynaud, Florence I, Popov, Sergey, Jones, Chris, Petrie, Kevin, Robinson, Simon P, Keun, Hector C and Chesler, Louis (2016) p53 Loss in MYC-Driven Neuroblastoma Leads to Metabolic Adaptations Supporting Radioresistance. Cancer research, 76 (10). pp. 3025-35. ISSN 1538-7445

Item Type: Article

Abstract

Neuroblastoma is the most common childhood extracranial solid tumor. In high-risk cases, many of which are characterized by amplification of MYCN, outcome remains poor. Mutations in the p53 (TP53) tumor suppressor are rare at diagnosis, but evidence suggests that p53 function is often impaired in relapsed, treatment-resistant disease. To address the role of p53 loss of function in the development and pathogenesis of high-risk neuroblastoma, we generated a MYCN-driven genetically engineered mouse model in which the tamoxifen-inducible p53ER(TAM) fusion protein was expressed from a knock-in allele (Th-MYCN/Trp53(KI)). We observed no significant differences in tumor-free survival between Th-MYCN mice heterozygous for Trp53(KI) (n = 188) and Th-MYCN mice with wild-type p53 (n = 101). Conversely, the survival of Th-MYCN/Trp53(KI/KI) mice lacking functional p53 (n = 60) was greatly reduced. We found that Th-MYCN/Trp53(KI/KI) tumors were resistant to ionizing radiation (IR), as expected. However, restoration of functional p53ER(TAM) reinstated sensitivity to IR in only 50% of Th-MYCN/Trp53(KI/KI) tumors, indicating the acquisition of additional resistance mechanisms. Gene expression and metabolic analyses indicated that the principal acquired mechanism of resistance to IR in the absence of functional p53 was metabolic adaptation in response to chronic oxidative stress. Tumors exhibited increased antioxidant metabolites and upregulation of glutathione S-transferase pathway genes, including Gstp1 and Gstz1, which are associated with poor outcome in human neuroblastoma. Accordingly, glutathione depletion by buthionine sulfoximine together with restoration of p53 activity resensitized tumors to IR. Our findings highlight the complex pathways operating in relapsed neuroblastomas and the need for combination therapies that target the diverse resistance mechanisms at play. Cancer Res; 76(10); 3025-35. ©2016 AACR.

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2016 p53 Loss in MYC-Driven Neuroblastoma Leads to Metabolic Adaptations Supporting Radioresistance Supplementary Materials and Methods.pdf - Supplemental Material
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2016 p53 Loss in MYC-Driven Neuroblastoma Leads to Metabolic Adaptations Supporting Radioresistance Supplementary Tables 1 through 3.pdf - Supplemental Material
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2016 p53 Loss in MYC-Driven Neuroblastoma Leads to Metabolic Adaptations Supporting Radioresistance Supplementary Figures 1 through 5 and Supplementary Figure Legends.pdf - Supplemental Material
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More Information

Depositing User: Kevin Petrie

Identifiers

Item ID: 12443
Identification Number: https://doi.org/10.1158/0008-5472.CAN-15-1939
ISSN: 1538-7445
URI: http://sure.sunderland.ac.uk/id/eprint/12443
Official URL: https://cancerres.aacrjournals.org/content/76/10/3...

Users with ORCIDS

ORCID for Kevin Petrie: ORCID iD orcid.org/0000-0002-9805-9152

Catalogue record

Date Deposited: 18 Aug 2020 19:07
Last Modified: 30 Sep 2020 10:49

Contributors

Author: Kevin Petrie ORCID iD
Author: Orli Yogev
Author: Karen Barker
Author: Arti Sikka
Author: Gilberto S Almeida
Author: Albert Hallsworth
Author: Laura M Smith
Author: Yann Jamin
Author: Ruth Ruddle
Author: Alexander Koers
Author: Hannah T Webber
Author: Florence I Raynaud
Author: Sergey Popov
Author: Chris Jones
Author: Simon P Robinson
Author: Hector C Keun
Author: Louis Chesler

University Divisions

Faculty of Health Sciences and Wellbeing > School of Medicine

Subjects

Sciences > Biomedical Sciences
Sciences > Health Sciences

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