EGFR is not a major driver for osteosarcoma cell growth in vitro but contributes to starvation and chemotherapy resistance

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.

Ursolic acid suppresses the biological function of osteosarcoma cells

“…In many types of cancer, including osteosarcoma, overexpression of EGFR is associated with aggressive invasiveness and resistance to therapy (24)(25)(26). Previous studies have indicated that EGFR may be an effective target for the treatment of human cancer (27,28).…”

EGFR is required for FOS‐dependent bone tumor development via RSK2/CREB signaling

“…EGFR inhibition in human OS cell lines has been shown to effectively decrease cell migration, cell invasion and colony formation (Messerschmitt et al , ). Other studies suggested that EGFR inhibition has no significant influence on cell proliferation, but enhances the anti‐tumor effects of starvation or chemotherapy‐induced cell stress in vitro (Sevelda et al , ). Our study shows that EGFR is a driver of OS, at least in a subgroup of patients suffering from EGFR and c‐Fos double‐positive tumors.…”

Cell apoptosis, autophagy and necroptosis in osteosarcoma treatment

“…Despite the improved prognosis, resistance to chemotherapy remains an obstacle in the treatment of osteosarcoma [51]. The identification of signals and effective agents that promote cell death may provide clues for developing new therapeutic strategies for chemoresistant osteosarcoma [52, 53]. Effective agents such as natural compounds, miRNA and proteins in treatment of osteosarcoma were summarized.…”