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Inhibition of Epidermal Growth Factor Receptor Improves Antitumor Efficacy of Vemurafenib in BRAF-mutant Human Melanoma in Preclinical Model

Inhibition of Epidermal Growth Factor Receptor Improves Antitumor Efficacy of Vemurafenib in BRAF-mutant Human Melanoma in Preclinical Model

István Kenessey, Zsófia Kramer, Lilla István, Mihály T Cserepes, Tamás Garay, Balázs Hegedűs, Judit Dobos, József Tímár, József Tóvári

Melanoma Res. 2018 Dec;28(6):536-546.

PMID: 30124539

Abstract:

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP257933827	Pelitinib		257933-82-7	Price

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