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

Br J Cancer. 2020 Mar;122(5):624-629. doi: 10.1038/s41416-019-0677-1. Epub 2019 Dec 20.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Brain Neoplasms / genetics
  • Brain Neoplasms / metabolism*
  • Brain Neoplasms / pathology
  • Brain Neoplasms / radiotherapy*
  • Cell Line, Tumor
  • DNA Damage
  • Glioma / genetics
  • Glioma / metabolism*
  • Glioma / pathology
  • Glioma / radiotherapy*
  • Humans
  • Immunohistochemistry
  • Neoplasm Grading
  • Pyrazoles / pharmacology
  • Radiation Tolerance / drug effects
  • Receptor, IGF Type 1 / antagonists & inhibitors
  • Receptor, IGF Type 1 / genetics
  • Receptor, IGF Type 1 / metabolism*
  • Signal Transduction / drug effects
  • Tissue Array Analysis
  • Triazines / pharmacology

Substances

  • BMS 754807
  • Pyrazoles
  • Triazines
  • Receptor, IGF Type 1