Cabozantinib Suppresses Tumor Growth and Metastasis in Hepatocellular Carcinoma by a Dual Blockade of VEGFR2 and MET

Abstract

Purpose: MET signaling has been suggested a potential role in hepatocellular carcinoma (HCC) and associated with prometastasis during antiangiogenesis therapy. We investigated the potential association between MET expression and therapeutic response to sorafenib in patients with HCC. Antitumor effects of cabozantinib, a dual inhibitor of MET and VEGFR2, were examined in cultured HCC cells as well as in vivo models.Experimental Design: Total MET and phosphorylated MET (p-MET) were measured in 29 resected HCC specimens, and correlated with response to sorafenib as postoperative adjuvant therapy. In the second set of experiments using cultured HCC cells, and mouse xenograft and metastatic models, effects of cabozantinib were examined.Results: High level of p-MET in resected HCC specimens was associated with resistance to adjuvant sorafenib therapy. In cultured HCC cells that expressed p-MET, cabozantinib inhibited the activity of MET and its downstream effectors, leading to G 1 -phase arrest. Cabozantinib inhibited tumor growth in p-METpositive and p-MET-negative HCC by decreasing angiogenesis, inhibiting proliferation, and promoting apoptosis, but it exhibited more profound efficacy in p-MET-positive HCC xenografts. Cabozantinib blocked the hepatocyte growth factor (HGF)-stimulated MET pathway and inhibited the migration and invasion of the HCC cells. Notably, cabozantinib reduced the number of metastatic lesions in the lung and liver in the experimental metastatic mouse model.Conclusions: Patients with HCC with high level of p-MET are associated with resistance to adjuvant sorafenib treatment. The dual blockade of VEGFR2 and MET by cabozantinib has significant antitumor activities in HCC, and the activation of MET in HCC may be a promising efficacy-predicting biomarker.

Chemotherapy and target therapy for hepatocellular carcinoma: New advances and challenges

“…Cabozantinib (XL184), a dual blockade of VEGFR2 and MET, inhibited tumor growth in HCC by decreasing angiogenesis, inhibiting proliferation and promoting apoptosis, but it exhibited more profound efficacy in phosphorylated-MET positive HCC xenografts [88] . A phase Ⅲ study of cabozantinib vs placebo in HCC patients who have received prior sorafenib (NCT01908426) is ongoing.…”

Cabozantinib for the treatment of renal cell carcinoma

“…In separate experiments in naïve mice, cabozantinib treatment inhibited phosphorylation of MET by HGF in liver tissue and phosphorylation of VEGFR2 by VEGF in lung tissue. Consistent with this activity, significant tumor growth inhibition or tumor regression after cabozantinib treatment has been observed in multiple tumor xenograft models including medullary thyroid cancer (MTC), breast cancer, hepatocellular carcinoma, lung carcinoma, and glioblastoma [13,22,23]. In a phase 3 trial, cabozantinib demonstrated efficacy compared with placebo in progressive, metastatic MTC, leading to approval in this indication [24].…”

Effects of Psoralen as an Anti-tumor Agent in Human Breast Cancer MCF-7/ADR Cells

“…And also, more complicated mechanisms still require further study by obtaining co-crystal structures of P-gp to explain the involving functional modulation of psoralen. 20) In recent years, many studies have found that MCF-7/ ADR with over-expression of P-gp showed stronger invasive ability and malignant potential compared to parental control MCF-7 cell possibly related to the loss of E-cadherin expression which is the epithelial marker. 21) This process is essentially dependent on the prominent biological event referred to as EMT 22,23) which enables cells of epithelial phenotype to generate mesenchymal derivatives.…”