Type 1 IGF receptor associates with adverse outcome and cellular radioresistance in paediatric high-grade glioma

Aaron D. Simpson,Olaf Ansorge,Chris Jones,Tamara Aleksic,Guillaume Rieunier,Valentine M. Macaulay,Ying Wei Jenetta Soo

doi:10.1038/s41416-019-0677-1

Abstract

High-grade glioma (HGG) is highly resistant to therapy, prompting us to investigate the contribution of insulin-like growth factor receptor (IGF-1R), linked with radioresistance in other cancers. IGF-1R immunohistochemistry in 305 adult HGG (aHGG) and 103 paediatric/young adult HGG (pHGG) cases revealed significant association with adverse survival in pHGG, with median survival of 13.5 vs 29 months for pHGGs with moderate/strong vs negative/weak IGF-1R (p = 0.011). Secondly, we tested IGF-1R inhibitor BMS-754807 in HGG cells, finding minimal radiosensitisation of 2/3 aHGG cell lines (dose enhancement ratios DERs < 1.60 at 2–8 Gy), and greater radiosensitisation of 2/2 pHGG cell lines (DERs ≤ 4.16). BMS-754807 did not influence radiation-induced apoptosis but perturbed the DNA damage response with altered induction/resolution of γH2AX, 53BP1 and RAD51 foci. These data indicate that IGF-1R promotes radioresistance in pHGG, potentially contributing to the association of IGF-1R with adverse outcome and suggesting IGF-1R as a candidate treatment target in pHGG.

Highlights

High-grade gliomas (HGGs) are treated with surgery, radiotherapy and in adults with concurrent and/or adjuvant temozolomide, but outcomes remain extremely poor.[1]
IGF receptors and ligands are expressed in HGGs,[5] and our data in other tumour types implicate IGF-1R in radioresistance via effects on the DNA damage response (DDR), influencing double strand break (DSB) repair by both non-homologous end-joining (NHEJ) and homologous recombination (HR).[6,7]
IGF-1R expression was significantly associated with adverse outcome in paediatric HGG (pHGG) but not in Adult HGG (aHGG)

Summary

Introduction

High-grade gliomas (HGGs) are treated with surgery, radiotherapy and in adults with concurrent and/or adjuvant temozolomide, but outcomes remain extremely poor.[1] Adult HGG (aHGG) and paediatric HGG (pHGG) are distinct at the molecular level with histone H3 gene mutation in ~50% of pHGG, while IDH and EGFR mutations are rare.[2,3] Factors implicated in treatment resistance include amplified signalling via receptor tyrosine kinases (RTKs) including the type 1 insulin-like growth factor receptor (IGF-1R), which signals via phosphatidylinositol 3-kinase (PI3K)-AKT and extracellular signalregulated kinases (ERKs) to promote proliferation and cell survival.[4] IGF receptors and ligands are expressed in HGGs,[5] and our data in other tumour types implicate IGF-1R in radioresistance via effects on the DNA damage response (DDR), influencing double strand break (DSB) repair by both non-homologous end-joining (NHEJ) and homologous recombination (HR).[6,7] it is unclear whether IGFs contribute to radioresistance in HGG

Methods

Results

Conclusion