Type 1 IGF receptor associates with adverse outcome and cellular radioresistance in paediatric high-grade glioma
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Published:2019-12-20
Issue:5
Volume:122
Page:624-629
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ISSN:0007-0920
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Container-title:British Journal of Cancer
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language:en
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Short-container-title:Br J Cancer
Author:
Simpson Aaron D., Soo Ying Wei Jenetta, Rieunier Guillaume, Aleksic Tamara, Ansorge Olaf, Jones Chris, Macaulay Valentine M.ORCID
Abstract
AbstractHigh-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.
Funder
DH | National Institute for Health Research The Rosetrees Trust and Stoneygate Trust (grant M515). Cancer Research UK National Institute for Health Research Biomedical Research Centre at The Royal Marsden and the Institute of Cancer Research The Rosetrees Trust and Stoneygate Trust (grant M515). National Institute for Health Research Oxford Biomedical Research Centre.
Publisher
Springer Science and Business Media LLC
Subject
Cancer Research,Oncology
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