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

Takeda,Tomoya; Tsubaki,Masanobu; Kato,Natsuki; Genno,Shuji; Ichimura,Eri; Enomoto,Aya; Imano,Motohiro; Satou,Takao; Nishida,Shozo

doi:10.3892/ol.2021.13089

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

Authors:
- Tomoya Takeda
- Masanobu Tsubaki
- Natsuki Kato
- Shuji Genno
- Eri Ichimura
- Aya Enomoto
- Motohiro Imano
- Takao Satou
- Shozo Nishida
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Affiliations: Department of Pharmacotherapy, Kindai University School of Pharmacy, Higashi‑Osaka, Osaka 577‑8502, Japan, Department of Surgery, Kindai University School of Medicine, Osakasayama, Osaka 589‑0014, Japan, Department of Pathology, Kindai University School of Medicine, Osakasayama, Osaka 589‑0014, Japan
Published online on: October 12, 2021 https://doi.org/10.3892/ol.2021.13089
Article Number: 827

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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.

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