Publications

BibTex format

@article{Yogev:2016:10.1158/0008-5472.CAN-15-1939,
author = {Yogev, O and Barker, K and Sikka, A and Almeida, GS and Hallsworth, A and Smith, LM and Jamin, Y and Ruddle, R and Koers, A and Webber, HT and Raynaud, FI and Popov, S and Jones, C and Petrie, K and Robinson, SP and Keun, HC and Chesler, L},
doi = {10.1158/0008-5472.CAN-15-1939},
journal = {Cancer Research},
pages = {3025--3035},
title = {p53 loss in MYC-driven neuroblastoma leads to metabolic adaptations supporting radioresistance},
url = {http://dx.doi.org/10.1158/0008-5472.CAN-15-1939},
volume = {76},
year = {2016}
}

Download

RIS format (EndNote, RefMan)

TY  - JOUR
AB  - 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 p53ERTAM fusion protein was expressed from a knock-in allele (Th-MYCN/Trp53KI). We observed no significant differences in tumor-free survival between Th-MYCN mice heterozygous for Trp53KI (n = 188) and Th-MYCN mice with wild-type p53 (n = 101). Conversely, the survival of Th-MYCN/Trp53KI/KI mice lacking functional p53 (n = 60) was greatly reduced. We found that Th-MYCN/Trp53KI/KI tumors were resistant to ionizing radiation (IR), as expected. However, restoration of functional p53ERTAM reinstated sensitivity to IR in only 50% of Th-MYCN/Trp53KI/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.
AU  - Yogev,O
AU  - Barker,K
AU  - Sikka,A
AU  - Almeida,GS
AU  - Hallsworth,A
AU  - Smith,LM
AU  - Jamin,Y
AU  - Ruddle,R
AU  - Koers,A
AU  - Webber,HT
AU  - Raynaud,FI
AU  - Popov,S
AU  - Jones,C
AU  - Petrie,K
AU  - Robinson,SP
AU  - Keun,HC
AU  - Chesler,L
DO  - 10.1158/0008-5472.CAN-15-1939
EP  - 3035
PY  - 2016///
SN  - 1538-7445
SP  - 3025
TI  - p53 loss in MYC-driven neuroblastoma leads to metabolic adaptations supporting radioresistance
T2  - Cancer Research
UR  - http://dx.doi.org/10.1158/0008-5472.CAN-15-1939
UR  - http://hdl.handle.net/10044/1/33217
VL  - 76
ER  -

Download

ProfessorHectorKeun

Contact

Location

Summary

Citation

BibTex format

RIS format (EndNote, RefMan)