Sorafenib treatment of metastatic melanoma with c‑Kit aberration reduces tumor growth and promotes survival

Abstract

Melanomas are highly malignant tumors that readily metastasize and have poor prognosis. Targeted therapy is a cornerstone of treatment for patients with melanoma. Although c-Kit gene aberration has found in 5-10% of melanoma cases, research on c-Kit inhibitors for melanoma with c-Kit aberration have been disappointing. Sorafenib is a tyrosine kinase inhibitor, whose targets include c-Kit, platelet derived growth factor receptor (PDGFR), VEGFR and RAF. The present study aimed to examine the effect of sorafenib on metastatic melanoma with c-Kit aberration. Cell viability was assessed via trypan blue assay. Migration and invasion were analyzed using cell culture inserts. The anti-metastatic effects and antitumour activity of sorafenib were determined in an in vivo model. Protein expression was detected via western blotting, and the expression of MMP and very late antigen (VLA) was detected via reverse transcription-quantitative PCR. It was identified that sorafenib decreased cell viability, migration and invasion in vitro. Furthermore, sorafenib inhibited metastasis and tumor growth in vivo. Mechanistically, sorafenib inhibited c-Kit, PDGFR, VEGFR, B-Raf and c-Raf phosphorylation both in vitro and in vivo. In addition, sorafenib reduced the expression levels of MMPs and VLA. Importantly, there was a significant effect of sorafenib treatment on overall survival in mice. Collectively, this study suggests that sorafenib may serve as a novel therapeutic option for melanoma with c-Kit dysregulation.Cells and culture conditions. Murine melanoma cell lines, B16F1 and B16BL6, were kindly provided by Dr Inufusa of Kindai University (Osaka, Japan). B16F1 cells were established from lung metastasis lesions from the intravenous injection of

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