p53 loss in Myc-driven neuroblastoma leads to metabolic adaptations supporting radioresistance

Citation

Yogev O, Barker K, Sikka A, Almeida GS, Hallsworth A, Smith LM, Jamin Y, Ruddle R, Koers A, Webber H, Raynaud FI, Popov S, Jones C, Petrie K, Robinson SP, Keun HC & Chesler L (2016) p53 loss in Myc-driven neuroblastoma leads to metabolic adaptations supporting radioresistance. Cancer Research, 76 (10), pp. 3025-3035. https://doi.org/10.1158/0008-5472.CAN-15-1939

Abstract
Neuroblastoma is the most common childhood extracranial solid tumor. In high-risk cases, many of which are characterized by amplification ofMYCN, 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 p53ERTAMfusion protein was expressed from a knock-in allele (Th-MYCN/Trp53KI). We observed no significant differences in tumor-free survival between Th-MYCNmice heterozygous forTrp53KI(n= 188) and Th-MYCNmice with wild-type p53 (n= 101). Conversely, the survival of Th-MYCN/Trp53KI/KImice lacking functional p53 (n= 60) was greatly reduced. We found that Th-MYCN/Trp53KI/KItumors were resistant to ionizing radiation (IR), as expected. However, restoration of functional p53ERTAMreinstated sensitivity to IR in only 50% of Th-MYCN/Trp53KI/KItumors, 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, includingGstp1andGstz1, 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.

Journal
Cancer Research: Volume 76, Issue 10