Differential responses of MET activations to MET kinase inhibitor and neutralizing antibody

Abstract

BackgroundAberrant MET tyrosine kinase signaling is known to cause cancer initiation and progression. While MET inhibitors are in clinical trials against several cancer types, the clinical efficacies are controversial and the molecular mechanisms toward sensitivity remain elusive.MethodsWith the goal to investigate the molecular basis of MET amplification (METamp) and hepatocyte growth factor (HGF) autocrine-driven tumors in response to MET tyrosine kinase inhibitors (TKI) and neutralizing antibodies, we compared cancer cells harboring METamp (MKN45 and MHCCH97H) or HGF-autocrine (JHH5 and U87) for their sensitivity and downstream biological responses to a MET-TKI (INC280) and an anti-MET monoclonal antibody (MetMab) in vitro, and for tumor inhibition in vivo.ResultsWe find that cancer cells driven by METamp are more sensitive to INC280 than are those driven by HGF-autocrine activation. In METamp cells, INC280 induced a DNA damage response with activation of repair through the p53BP1/ATM signaling pathway. Although MetMab failed to inhibit METamp cell proliferation and tumor growth, both INC280 and MetMab reduced HGF-autocrine tumor growth. In addition, we also show that HGF stimulation promoted human HUVEC cell tube formation via the Src pathway, which was inhibited by either INC280 or MetMab. These observations suggest that in HGF-autocrine tumors, the endothelial cells are the secondary targets MET inhibitors.ConclusionsOur results demonstrate that METamp and HGF-autocrine activation favor different molecular mechanisms. While combining MET TKIs and ATM inhibitors may enhance the efficacy for treating tumors harboring METamp, a combined inhibition of MET and angiogenesis pathways may improve the therapeutic efficacy against HGF-autocrine tumors.Electronic supplementary materialThe online version of this article (10.1186/s12967-018-1628-y) contains supplementary material, which is available to authorized users.

Receptor tyrosine kinases as druggable targets in glioblastoma: Do signaling pathways matter?

“… 84 Functionally, INCB28060 showed potent inhibition of MET-mediated signaling cascades in various cancer cells, and preferentially inhibited tumors with MET amplification. 84 , 85 Currently, a phase I clinical trial is evaluating the safety and efficacy of the combination of INC28060 and bevacizumab in GBM patients with previous treatment and those with unresectable GBM (NCT02386826). Cabozantinib (XL184) is a multitarget TKI with potent activity against MET and VEGFR2 and is FDA approved for treating hepatocellular carcinoma patients previously treated with sorafenib, a VEGF inhibitor.…”

Capmatinib in Japanese patients with MET exon 14 skipping–mutated or MET‐amplified advanced NSCLC: GEOMETRY mono‐1 study

“…MET Δex14 is also associated with a poor prognosis of NSCLC, 4,5,13,19‐23 and patients carrying this mutation typically show poor responses to standard therapies including immunotherapies in patients with high programmed death ligand‐1 expression or a high tumor mutational burden 4,5,22,24‐28 . Therefore, there is strong rationale for using MET inhibitors to treat MET Δex14‐mutated NSCLC as well as MET ‐amplified NSCLC 29‐31 …”

A Biparatopic Antibody That Modulates MET Trafficking Exhibits Enhanced Efficacy Compared with Parental Antibodies in MET-Driven Tumor Models

“…Given that MET appears to be a cancer driver primarily when mutated or amplified, the onartuzumab clinical failures likely resulted from the fact that these trials did not select for cancers that harbor MET genetic alterations. Furthermore, onartuzumab appears to be a poor blocker of ligand-independent MET signaling (14), which would limit its efficacy in MET-amplified cancers.…”