Epidermal Growth Factor Receptor: Is It a Feasible Target for the Treatment of Osteosarcoma?

Abstract

PurposeFeatures of epidermal growth factor receptor (EGFR) expression in osteosarcoma and in vitro efficacies of EGFR inhibitors against osteosarcoma cells were evaluated.Materials and MethodsThirty biopsy samples of osteosarcoma patients were retrospectively analyzed for EGFR protein expression by immunohistochemistry. Relationships between EGFR expression and clinicopathologic characteristics and treatment outcomes were evaluated. Four osteosarcoma cell lines were analyzed for EGFR and p-EGFR expression by western blotting. Efficacies of gefitinib and BIBW2992 on osteosarcoma cells were evaluated using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Tyrosine kinase domains in exons 18 to 21 were sequenced and gene expression analyses of EGFR and PTEN were performed in four osteosarcoma cell lines.ResultsEGFR protein was expressed in 27 (90%) samples (6 low, 12 intermediate, 9 high) and in three cell lines. Intermediate or high staining for EGFR was related to a tumor volume<150 mL (p<0.001) and histologic subtype other than osteoblastic type (p=0.03). However, EGFR expression was not associated with histologic response to preoperative chemotherapy or survival. Gefitinib and BIBW 2992 did not have any significant inhibitory effect on cell viabilities. DNA sequencing analysis revealed three osteosarcoma cell lines have single base changes at codon 2361 of exon 20 (G to A), without affecting translation results. Furthermore, no mutation was found to be associated with constitutive EGFR activation.ConclusionIn the present study, gefitinib and BIBW2992 were not effective against osteosarcoma cells. However, as osteosarcoma cells express EGFR, further studies are necessary to explore the potential of other therapeutic agents targeting EGFR.

Clinical Predictive Value of Serum Angiogenic Factor in Patients with Osteosarcoma

“…The histological feature is the formation of osteoid tissue. The disease metastasizes in early stage and minimal pulmonary metastasis occurs in 80% of patients (Lee et al, 2012). Microvessel consist of tiny vessels and capillaries, the distribution of microvessel of carcinoma is among oncocyte.…”

The Use of Molecular Pathway Inhibitors in the Treatment of Osteosarcoma

“…Additionally, 90% of 27 OS biopsy samples showed moderate-to-high EGFR protein levels, as well as in four established OS cell lines HOS, KHOS/NP, MG-63, and U-2 OS . EGFR expression was not found to correlate to response to preoperative chemotherapy or survival [58]. Another group demonstrated that OS cell lines, MG-63 and Saos-2 proliferative abilities, were decreased by natural lavonoid Icariside II.…”

ErbB Receptors as Prognostic and Therapeutic Drug Targets in Bone and Soft Tissue Sarcomas

“…The expression of ErbB1 has been reported in 30-90% of tumor tissues (26)(27)(28); however, correlations between ErbB1 expression and clinical prognosis have been controversial. The study by Kersting et al (29) found that all patients with strong ErbB1 expression were alive for up to 12 years after diagnosis (overall survival), irrespective of the degree of neoadjuvant chemotherapy and induced tumor regression, which indicted that expression of ErbB1 in high-grade osteosarcoma showed a positive dose-response relation with favorable clinical outcome.…”

“…Wu et al (31) performed a clinical study and constructed a mediation model to explain and confirm the correlation pattern of ErbB1 and the AKT signal pathway for cancer cell proliferation in osteosarcoma patients. Lee et al (28) found that loss of PTEN in tumors with ErbB1 expression was associated with resistance to anti-ErbB1 tyrosine kinase inhibitors. However, Freeman et al (33) did not identify a correlation between ErbB1 expression, or PTEN, and clinical features.…”

“…Studies of ErbB1 gene mutations identify a point mutation at codon 863 in exon 21, E829E, and R831C in exon 21 (36,41) (36,37). Of all of these mutations, only one mutation (R831C in exon 21) resulted in an amino acid change from arginine to cysteine (28,33,34). Furthermore, the methylation status of ERBB1 CpG island was examined in osteosarcomas.…”