2ME2 inhibits the activated hypoxia-inducible pathways by cabozantinib and enhances its efficacy against medullary thyroid carcinoma

摘要: Cabozantinib is a multi-targeted tyrosine kinase inhibitor targeting vascular endothelial growth factor (VEGF) receptor (VEGFR)-2, MET (c-Met, also called hepatocyte (HGF) receptor), and other kinases. has recently been approved for treating advanced medullary thyroid carcinoma (MTC), but its long-term benefit remains uncertain dose-dependent adverse events are very common. The present study demonstrated that 2-methoxyestradiol (2ME2), an of hypoxia-inducible factors (HIFs) promising anticancer agent under investigation in clinical trials, strengthens activities cabozantinib against MTC cells vitro vivo. activated pathways, which mainly regulated by HIF-1, contribute to the resistance hypoxic cabozantinib. upregulated HIF-1α expression at translational levels increased downstream including VEGF, lactate dehydrogenase A (LDHA), HGF, MET. 2ME2 corrected pathways through downregulating inhibiting nuclear translocation cells. Administration enhanced efficacy suppressing cell line xenografts patient-derived established mice. Given targets insensitive cancer can inhibit cabozantinib, results warrant further 2ME2, particularly combination with treatment MTC.