Emerging molecular targets in oncology: clinical potential of MET/hepatocyte growth-factor inhibitors.

87 , 115 However, awareness of toxicity related to off-target effects, such as those on VEGFR (hypertension, hemorrhage, perforation) is also necessary as these may be significant. 115 Additionally, tivantinib appears to have cytotoxic effects that are independent of its MET-inhibitory activity and significant rates of neutropenia and neutropenia-related deaths have been documented with the use of this compound. 100 , 132 Resistance to MET inhibition Acquisition of novel mutations, redundancy in intracellular signaling pathways, and downregulation of inhibitory feedback mechanisms have been demonstrated to be responsible for de novo and acquired resistance to other TKIs, such as those inhibiting EGFR, BRAF and mitogen-activated protein-kinase kinase (MEK).

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