Inhibition of EGFR improves antitumor efficacy of vemurafenib in BRAF-mutant human melanoma in preclinical model

Kenessey, István and Kramer, Zsófia and István, Lilla and Garay, Tamás and Hegedűs, Balázs and Dobos, Judit and Tímár, József and Tóvári, József (2016) Inhibition of EGFR improves antitumor efficacy of vemurafenib in BRAF-mutant human melanoma in preclinical model. BMC CANCER. ISSN 1471-2407 (Unpublished)

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Abstract

Background: Oncogenic activation of the epidermal growth factor receptor (EGFR) signaling pathway occurs in a variety tumour types, albeit in human melanoma the contribution of EGFR is still unclear. Methods: The potential role of EGFR was analyzed in four BRAF-mutant, one NRAS-mutant and one wild-type NRAS-BRAF-carrying human melanoma cell lines. We have tested clinically available reversible tyrosine kinase inhibitors (TKI) gefitinib and erlotinib, irreversible EGFR-TKI pelitinib and a reversible experimental compound (PD153035) on in vitro proliferation, apoptosis, migration as well as in vivo metastatic colonization in a spleen-liver model. Results: The presence of the intracellular domain of EGFR protein and its constitutive activity were demonstrated in all cell lines. We detected significant differences between the efficacies of EGFR-TKIs, irreversible inhibition had the strongest anti-tumour potential. Compared to BRAF-mutant cells, wild-type BRAF associated with relative resistance against gefitinib. In combination with gefitinib, selective mutant BRAF-inhibitor vemurafenib showed additive effect in BRAF-mutant cell lines. Treatment of BRAF-mutant cells with gefinib- or pelitinib attenuated in vitro cell migration and in vivo colonization. Conclusions: Our preclinical data suggest that EGFR is a potential target in the therapy of BRAF-mutant malignant melanoma; however, more benefits could be expected from irreversible EGFR-TKIs and combined treatment settings.

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