Reduced EGFR and increased miR-221 is associated with increased resistance to temozolomide and radiotherapy in glioblastoma

Despite aggressive treatment with temozolomide and radiotherapy and extensive research into alternative therapies there has been little improvement in Glioblastoma patient survival. Median survival time remains between 12 and 15 months mainly due to treatment resistance and tumor recurrence. In this...

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Bibliographic Details
Published in:Scientific reports 2020-10, Vol.10 (1), p.17768, Article 17768
Main Authors: Areeb, Zammam, Stuart, Sarah F., West, Alice J., Gomez, Juliana, Nguyen, Hong P. T., Paradiso, Lucia, Zulkifli, Ahmad, Jones, Jordan, Kaye, Andrew H., Morokoff, Andrew P., Luwor, Rodney B.
Format: Article
Language:English
Subjects:
631/80/86
692/4028/67/1059/2326
692/699/67/395
Antineoplastic Agents - pharmacology
Apoptosis
Brain Neoplasms - drug therapy
Brain Neoplasms - genetics
Cell Line, Tumor
Chemoradiotherapy - methods
Drug Resistance, Neoplasm - genetics
ErbB Receptors - genetics
ErbB Receptors - metabolism
Gene Expression Regulation, Neoplastic
Glioblastoma - drug therapy
Glioblastoma - genetics
Humanities and Social Sciences
Humans
MicroRNAs - genetics
multidisciplinary
Neoplasm Recurrence, Local
Science
Science (multidisciplinary)
Signal Transduction
Temozolomide - pharmacology
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Summary:Despite aggressive treatment with temozolomide and radiotherapy and extensive research into alternative therapies there has been little improvement in Glioblastoma patient survival. Median survival time remains between 12 and 15 months mainly due to treatment resistance and tumor recurrence. In this study, we aimed to explore the underlying mechanisms behind treatment resistance and the lack of success with anti-EGFR therapy in the clinic. After generating a number of treatment resistant Glioblastoma cell lines we observed that resistant cell lines lacked EGFR activation and expression. Furthermore, cell viability assays showed resistant cells were significantly less sensitive to the anti-EGFR agents when compared to parental cell lines. To further characterise the resistance mechanism in our cells microRNA prediction software identified miR-221 as a negative regulator of EGFR expression. miR-221 was up-regulated in our resistant cell lines, and this up-regulation led to a significant reduction in EGFR expression in both our cultured cell lines and a large cohort of glioblastoma patient tumor tissue.
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-020-74746-x