The dual blockade of MET and VEGFR2 signaling demonstrates pronounced inhibition on tumor growth and metastasis of hepatocellular carcinoma

Abstract

BackgroundThe application of VEGF signaling inhibitors have been associated with more invasive or metastatic behavior of cancers including hepatocellular carcinoma (HCC). We explored the contribution of MET pathway to the enhanced HCC invasion and metastasis by VEGF signaling inhibition, and investigated the antitumor effects of NZ001, a novel dual inhibitor of MET and VEGFR2, in HCC.MethodsImmunocompetent orthotopic mice model of hepal-6 was established to investigate the effects of either VEGF antibody alone or in combination with the selective MET inhibitor on tumor aggressiveness. The antitumor effects of NZ001 were examined in cultured HCC cells as well as in vivo models. MET gene amplification was determined by SNP 6.0 assay. MET/P-MET expression was detected by IHC.ResultsSelective VEGF signaling inhibition by VEGF antibody significantly reduced in vivo tumor growth of the orthotopic mice models, simultaneously also enhanced tumor invasion and metastasis, but inhibiting MET signaling attenuated this side-effect. Further study revealed that hypoxia caused by VEGF signaling inhibition induced HIF-1α nuclear accumulation, subsequently leading to elevated total-MET expression, and synergized with HGF in inducing invasion. NZ001, a novel dual inhibitor of MET and VEGFR2, markedly inhibited both tumor growth and metastasis of HCC, which showed obvious advantages over sorafenib in not inducing more invasive and metastatic behaviors. This effect is more pronounced in HCC with MET amplification and overexpression.ConclusionsThe activation of MET is responsible for the metastasis-promoting effects induced by VEGF inhibition. MET and VEGFR2 dual blockade, NZ001, has advantages over sorafenib in not inducing more invasive and metastatic behaviors; MET amplification and overexpression can be used to identify the subgroup of patients most likely to get the optimal benefit from NZ001 treatment.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0750-2) contains supplementary material, which is available to authorized users.

Identification of the Novel Oncogenic Role of SAAL1 and Its Therapeutic Potential in Hepatocellular Carcinoma

“…The main mechanisms of drug resistance to sorafenib include the activation of PI3K/Akt or Met signaling pathways [27][28][29][30][31]. Therefore, the Met kinase inhibitor, such as foretinib, has been suggested as a treatment option after sorafenib resistance in HCC patients [25,32]. Our data showed that inhibition of SAAL1 expression could lead to a reduction in HGF-induced PI3K/Akt/mTOR phosphorylation cascade.…”

The Function of the HGF/c-Met Axis in Hepatocellular Carcinoma

“…Moreover, the intact and normal HGF/c-Met signaling is elementary for sustaining normal redox homeostasis and could suppress tumor in the N-nitrosodiethylamine-induced HCC (Takami et al, 2007). Additionally, c-Met may induce VEGF-A expression, which can enhance tumor angiogenesis Zhang et al, 2018b).…”

The Efficacy of Ramucirumab in the Treatment of Gastric or Gastroesophageal Junction Cancer: A Meta-Analysis of RCTs

“…This may provide an explanation for why the RAM add-on therapy did not provide significantly prolonged median OS and PFS rates in some clinical trials. Zhang et al [ 36 ] demonstrated that the inhibition of both VEGFR-2 and MET yielded a more promising effect on suppressing tumor growth and metastasis in hepatocellular carcinoma than blocking VEGFR-2 did. This may provide evidence for further therapy approaches for the combination medication of VEGFR-2 and MET inhibition.…”