Type 1 IGF receptor associates with adverse outcome and cellular radioresistance in paediatric high-grade glioma.
Aaron D SimpsonYing Wei Jenetta SooGuillaume RieunierTamara AleksicOlaf AnsorgeChris JonesValentine Moya MacaulayPublished in: British journal of cancer (2019)
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.
Keyphrases
- induced apoptosis
- binding protein
- dna damage response
- growth hormone
- high grade
- pi k akt
- signaling pathway
- endoplasmic reticulum stress
- emergency department
- intensive care unit
- oxidative stress
- young adults
- cell cycle arrest
- low grade
- electronic health record
- stem cells
- radiation therapy
- cell proliferation
- machine learning
- deep learning
- big data
- drug induced