dc.contributor.author | Yogev, O | |
dc.contributor.author | Barker, K | |
dc.contributor.author | Sikka, A | |
dc.contributor.author | Almeida, GS | |
dc.contributor.author | Hallsworth, A | |
dc.contributor.author | Smith, LM | |
dc.contributor.author | Jamin, Y | |
dc.contributor.author | Ruddle, R | |
dc.contributor.author | Koers, A | |
dc.contributor.author | Webber, HT | |
dc.contributor.author | Raynaud, FI | |
dc.contributor.author | Popov, S | |
dc.contributor.author | Jones, C | |
dc.contributor.author | Petrie, K | |
dc.contributor.author | Robinson, SP | |
dc.contributor.author | Keun, HC | |
dc.contributor.author | Chesler, L | |
dc.date.accessioned | 2019-09-19T08:48:35Z | |
dc.date.issued | 2016-09-29 | |
dc.identifier.citation | Cancer research, 2016, 76 (10), pp. 3025 - 3035 | |
dc.identifier.issn | 0008-5472 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/3351 | |
dc.identifier.eissn | 1538-7445 | |
dc.identifier.doi | 10.1158/0008-5472.can-15-1939 | |
dc.description.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. | |
dc.format | Print-Electronic | |
dc.format.extent | 3025 - 3035 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | AMER ASSOC CANCER RESEARCH | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.subject | Animals | |
dc.subject | Mice, Transgenic | |
dc.subject | Humans | |
dc.subject | Mice | |
dc.subject | Neuroblastoma | |
dc.subject | RNA, Messenger | |
dc.subject | Blotting, Western | |
dc.subject | Immunoenzyme Techniques | |
dc.subject | Reverse Transcriptase Polymerase Chain Reaction | |
dc.subject | Adaptation, Physiological | |
dc.subject | Apoptosis | |
dc.subject | Cell Proliferation | |
dc.subject | Radiation, Ionizing | |
dc.subject | Radiation Tolerance | |
dc.subject | Female | |
dc.subject | Male | |
dc.subject | Tumor Suppressor Protein p53 | |
dc.subject | Real-Time Polymerase Chain Reaction | |
dc.subject | N-Myc Proto-Oncogene Protein | |
dc.title | p53 Loss in MYC-Driven Neuroblastoma Leads to Metabolic Adaptations Supporting Radioresistance. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2016-02-09 | |
rioxxterms.versionofrecord | 10.1158/0008-5472.can-15-1939 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2016-05 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Cancer research | |
pubs.issue | 10 | |
pubs.notes | Not known | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group) | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Glioma Team | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Paediatric Solid Tumour Biology and Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Paediatric Solid Tumour Biology and Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Glioma Team | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Paediatric Solid Tumour Biology and Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Pre-Clinical MRI | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group) | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Glioma Team | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Paediatric Solid Tumour Biology and Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Paediatric Solid Tumour Biology and Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Glioma Team | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Paediatric Solid Tumour Biology and Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Pre-Clinical MRI | |
pubs.publication-status | Published | |
pubs.volume | 76 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group) | |
icr.researchteam | Glioma Team | |
icr.researchteam | Paediatric Solid Tumour Biology and Therapeutics | |
icr.researchteam | Pre-Clinical MRI | |
dc.contributor.icrauthor | Jamin, Yann | |
dc.contributor.icrauthor | Ruddle, Ruth | |
dc.contributor.icrauthor | Raynaud, Florence | |
dc.contributor.icrauthor | Jones, Chris | |
dc.contributor.icrauthor | Robinson, Simon | |
dc.contributor.icrauthor | Chesler, Louis | |