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Inhibition of epidermal growth factor receptor improves antitumor efficacy of vemurafenib in BRAF-mutant human melanoma in preclinical model

Kenessey, Istvána,b; Kramer, Zsófiaa; István, Lillaa; Cserepes, Mihály T.c,d,e; Garay, Tamása; Hegedűs, Balázsf; Dobos, Juditg; Tímár, Józsefa,f; Tóvári, Józsefc

doi: 10.1097/CMR.0000000000000488
ORIGINAL ARTICLES: Translational research

Oncogenic activation of the epidermal growth factor receptor (EGFR) signaling pathway occurs in a variety of tumor types, albeit in human melanoma, the contribution of EGFR is still unclear. 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 (TKIs) 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. The presence of the intracellular domain of EGFR protein and its constitutive activity were demonstrated in all cell lines. Efficacies of EGFR-TKIs showed significant differences, and irreversible inhibition had the strongest antitumor potential. Compared with BRAF-mutant cells, wild-type BRAF was associated with relative resistance against gefitinib. In combination with gefitinib, selective mutant BRAF-inhibitor vemurafenib showed additive effect in all BRAF-mutant cell lines. Treatment of BRAF-mutant cells with gefitinib or pelitinib attenuated in-vitro cell migration and in-vivo colonization. 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.

a2nd Department of Pathology, Semmelweis University

bHungarian Cancer Registry, National Institute of Oncology

cDepartment of Experimental Pharmacology, National Institute of Oncology

dInstitute of Enzymology, Research Center for Natural Sciences, Hungarian Academy of Sciences

eSemmelweis University

fHungarian Academy of Sciences, Molecular Oncology Research Group, Semmelweis University

gVichem Chemie Ltd, Budapest, Hungary

Correspondence to István Kenessey, MD, PhD, 2nd Department of Pathology, Semmelweis University, Üllői út 93, Budapest H-1091, Hungary Tel: +36 1 215 7300/53460; fax: +36 1 215 6921; e-mail: steveken12@yahoo.com

Received September 19, 2017

Accepted June 28, 2018

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