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

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 reve...

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Vydáno v:British journal of cancer Ročník 122; číslo 5; s. 624 - 629
Hlavní autoři: Simpson, Aaron D., Soo, Ying Wei Jenetta, Rieunier, Guillaume, Aleksic, Tamara, Ansorge, Olaf, Jones, Chris, Macaulay, Valentine M.
Médium: Journal Article
Jazyk:angličtina
Vydáno: London Nature Publishing Group UK 01.03.2020
Nature Publishing Group
Témata:
631/67/1922
692/4028/67/1922
Apoptosis
Biomedical and Life Sciences
Biomedicine
Brain Neoplasms - genetics
Brain Neoplasms - metabolism
Brain Neoplasms - pathology
Brain Neoplasms - radiotherapy
Brief Communication
Cancer Research
Cell Line, Tumor
Cell lines
DNA Damage
Drug Resistance
Epidemiology
Glioma
Glioma - genetics
Glioma - metabolism
Glioma - pathology
Glioma - radiotherapy
Humans
Immunohistochemistry
Insulin
Insulin-like growth factors
Molecular Medicine
Neoplasm Grading
Oncology
Pediatrics
Pyrazoles - pharmacology
Radiation Tolerance - drug effects
Radioresistance
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
ISSN:0007-0920, 1532-1827, 1532-1827
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Shrnutí: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.
Bibliografie:ObjectType-Article-1
SourceType-Scholarly Journals-1
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ISSN:0007-0920
1532-1827
1532-1827
DOI:10.1038/s41416-019-0677-1