p53 Loss in MYC-Driven Neuroblastoma Leads to Metabolic Adaptations Supporting Radioresistance.
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Date
2016-09-29ICR Author
Author
Yogev, O
Barker, K
Sikka, A
Almeida, GS
Hallsworth, A
Smith, LM
Jamin, Y
Ruddle, R
Koers, A
Webber, HT
Raynaud, FI
Popov, S
Jones, C
Petrie, K
Robinson, SP
Keun, HC
Chesler, L
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Subject
Animals
Mice, Transgenic
Humans
Mice
Neuroblastoma
RNA, Messenger
Blotting, Western
Immunoenzyme Techniques
Reverse Transcriptase Polymerase Chain Reaction
Adaptation, Physiological
Apoptosis
Cell Proliferation
Radiation, Ionizing
Radiation Tolerance
Female
Male
Tumor Suppressor Protein p53
Real-Time Polymerase Chain Reaction
N-Myc Proto-Oncogene Protein
Research team
Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group)
Glioma Team
Paediatric Solid Tumour Biology and Therapeutics
Pre-Clinical MRI
Language
eng
Date accepted
2016-02-09
License start date
2016-05
Citation
Cancer research, 2016, 76 (10), pp. 3025 - 3035
Publisher
AMER ASSOC CANCER RESEARCH