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Fig. 6 | Journal of Translational Medicine

Fig. 6

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

Fig. 6

Proposed mechanisms of MET inhibitors in METamp and HGF-autocrine tumors. a METamp tumors are driven by receptor dimerization that is independent of HGF stimulation. They are sensitive to TKIs targeting MET intracellularly, but not to neutralizing antibodies interfering with extracellular ligand–receptor binding. In these tumors, constitutive inhibition of the MET signaling pathway may cause DSBs (i.e., via generation of reactive oxygen species, ROS) followed by DNA repair through the NHEJ process. Acquired resistance may occur through secondary chromosomal rearrangement via NHEJ. Combination of MET inhibitors with DNA repair inhibitors may enhance the therapeutic efficacy. b HGF-autocrine tumors are driven by endogenous HGF stimulation and are sensitive to both MET TKIs and neutralizing antibodies. Tumor-derived HGF further stimulates endothelial cells for neovasculature, which are the secondary targets in addition to the tumor cells. Acquired resistance may occur through MET signaling by-pass via other receptor tyrosine kinases, such as EGFR [48]; the micro-environmental response also plays an essential role. Combination with angiogenic inhibitors may enhance the therapeutic efficacy

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