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Effects of epidermal growth factor receptor kinase inhibition on radiation response in canine osteosarcoma cells

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Title: Effects of epidermal growth factor receptor kinase inhibition on radiation response in canine osteosarcoma cells
Author: Mantovani, Fernanda
Department: Department of Clinical Studies
Program: Clinical Studies
Advisor: Mutsaers, Anthony
Abstract: Radiation therapy for canine osteosarcoma promotes transient improvement in analgesia. The addition of sensitizing agents may enhance tumour response to radiation therapy, improving patient outcomes. The epidermal growth factor receptor (EGFR) is expressed in canine osteosarcoma and correlated to prognosis. This research evaluated the effects of the EGFR inhibitor erlotinib on canine osteosarcoma cell radiation responses, target and downstream protein expression in vitro. The impact of this treatment on levels of vascular endothelial growth factor (VEGF) was also investigated. Clonogenic survival and cell viability assays were performed after treatment with erlotinib as a single agent and in combination with radiation at doses of 2-10 Gy on three canine osteosarcoma cell lines. Target and downstream protein expression was assessed by Western blot after treatment with erlotinib as a single agent or in combination with 2 Gy radiation. Levels of VEGF in conditioned media were measured by enzyme-linked immunosorbent assay (ELISA). Radiation at doses of 2-10 Gy demonstrated a dose dependent reduction in clonogenic survival in all cell lines. Erlotinib treatment reduced clonogenic survival in two and enhanced the impact of radiation in one of three cell lines. In cell viability assays, erlotinib exhibited single agent activity in one cell line at 10 uM dose, and in all three cell lines at 40 uM dose. Erlotinib at 40 uM demonstrated radiation enhancement effects at 2 and 4 Gy for all cell lines. Erlotinib did not alter total levels of EGFR, nor inhibit downstream protein kinase B (PKB/Akt) activation. On the contrary, erlotinib treatment increased phosphorylated Akt in two of three cell lines. Levels of VEGF in conditioned media increased after erlotinib treatment as a single agent and in combination with radiation in two of three cell lines, and decreased with erlotinib treatment in the third cell line. Erlotinib treatment promoted modest enhancement of radiation effects in canine osteosarcoma cells, and possessed activity as a single agent, indicating a potential role for EGFR inhibition in the treatment of a subset of osteosarcoma patients. EGFR signalling and angiogenic responses to radiation and erlotinib are likely to be multifactorial and require further investigation.
URI: http://hdl.handle.net/10214/9503
Date: 2016-01


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