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مریم اعظم حسین زاده، سیده نگین موسوی نژاد، فاطمه بهنام رسولی

Background: Melanoma is an aggressive skin cancer with increasing incidence rates. In melanoma cells, hepatocyte growth factor (HGF) is continuously produced, activating the c-MET receptor, a tyrosine kinase encoded by the MET proto-oncogene. This activation triggers multiple signaling pathways, including PI3K-AKT, STAT, SRC, and MAPK. Foretinib is an oral multikinase inhibitor that primarily targets the HGF/MET signaling pathway by binding to c-MET, reducing its phosphorylation, and inhibiting tumor cell proliferation. Foretinib has been studied in various clinical trials for different cancer types. The aim of present study was to investigate whether Foretinib could be considered as a potent agent for targeting MET in metastatic melanoma. Methods: For computational analysis, target prediction of Foretinib was obtained from SuperPred online tool using the isomeric SMILES code from PubChem. Meanwhile, genes related to metastatic melanoma were obtained from the GeneCards database. Then, Venn diagram was constructed to define overlaying targets for Foretinib and metastatic melanoma. Furthermore, the STRING database and Cytoscape software were utilized for protein-protein interaction and gene set enrichment analyses. Moreover, the expression of MET was validated in melanoma tissue using TNMplot and UALCAN online tools. Lastly, the binding affinity of Foretinib with MET was predicted by molecular docking studies. Results: MET was identified as a common target for Foretinib and metastatic melanoma. The involvement of MET in various cellular components (CC) and biological processes (BP) was confirmed by enrichment studies. Additionally, expression analyses of MET revealed its upregulation in metastatic melanoma samples, and also a negative correlation was found for MET expression and patient overall survival. Molecular docking indicated the favorable interaction of Foretinib with MET with -2.7136 JAMDA score, and key residues involved in the interaction were Lys1244, Ser1236, Tyr1234, Val1237, Thr1289 and His1238. Conclusions: Due to the overexpression of MET in metastatic melanoma, and favorable interaction of Foretinib with MET protein, this small molecule could be considered as a potent agent to target this protein and be used for novel therapeutic approaches.

Foretinib, Metastatic Melanoma, MET, Molecular docking

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اعظم حسین زاده، مریم، نگین موسوی نژاد، سیده، بهنام رسولی، فاطمه، 1404، دیدگاه های ساز و کاری میانکنش Foretinib با MET : بررسی فعالیت ضد سرطانی در ملانوما متاستاتیک، کنگره بین المللی زیست پزشکی سرطان و سلولهای بنیادی، http://conf.sums.ac.ir/fa/archive_index.php?c=HN-icsbc1&aid=1514205