Abstract
BackgroundEnhanced signalling via the epidermal growth factor receptor (EGFR) is a hallmark of multiple human carcinomas. However, in recent years data have accumulated that EGFR might also be hyperactivated in human sarcomas. Aim of this study was to investigate the influence of EGFR inhibition on cell viability and its interaction with chemotherapy response in osteosarcoma cell lines.MethodsWe have investigated a panel of human osteosarcoma cell lines regarding EGFR expression and downstream signalling. To test its potential applicability as therapeutic target, inhibition of EGFR by gefitinib was combined with osteosarcoma chemotherapeutics and cell viability, migration, and cell death assays were performed.ResultsOsteosarcoma cells expressed distinctly differing levels of functional EGFR reaching in some cases high amounts. Functionality of EGFR in osteosarcoma cells was proven by EGF-mediated activation of both MAPK and PI3K/AKT pathway (determined by phosphorylation of ERK1/2, AKT, S6, and GSK3β). The EGFR-specific inhibitor gefitinib blocked EGF-mediated downstream signal activation. At standard in vitro culture conditions, clinically achievable gefitinib doses demonstrated only limited cytotoxic activity, however, significantly reduced long-term colony formation and cell migration. In contrast, under serum-starvation conditions active gefitinib doses were distinctly reduced while EGF promoted starvation survival. Importantly, gefitinib significantly supported the anti-osteosarcoma activities of doxorubicin and methotrexate regarding cell survival and migratory potential.ConclusionOur data suggest that EGFR is not a major driver for osteosarcoma cell growth but contributes to starvation- and chemotherapy-induced stress survival. Consequently, combination approaches including EGFR inhibitors should be evaluated for treatment of high-grade osteosarcoma patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-015-0251-5) contains supplementary material, which is available to authorized users.
Highlights
Enhanced signalling via the epidermal growth factor receptor (EGFR) is a hallmark of multiple human carcinomas
The respective EGFR mRNA was detectable by real-time polymerase chain reaction (PCR) in all osteosarcoma cell lines (Fig. 1a) and correlated roughly with membrane-residing EGFR levels
EGFR gene expression levels are opposed to histological subtype and the well known predictive osteosarcoma biomarker ABCB1 (P-glycoprotein) [4] in Additional file 1: Table S1
Summary
Enhanced signalling via the epidermal growth factor receptor (EGFR) is a hallmark of multiple human carcinomas. In recent years data have accumulated that EGFR might be hyperactivated in human sarcomas. The long-term survival of patients with osteosarcoma has improved from 10 to 20 % to nearly 80 % within the last 25 years, due to the use of neoadjuvant chemotherapy [1]. This plateau has not changed for more than 15 years [2]. For patients with metastatic disease, the outcomes are distinctly worse, with less than 30 % survival at 5 years [3]. There is still an urgent demand for new and more effective therapeutic strategies
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