MET as a possible target for non-small-cell lung cancer

Abstract

Lung cancer is a heterogeneous group of disorders that is now being subdivided into molecular subtypes with dedicated targeted therapies. The MET receptor tyrosine kinase has been identified as aberrantly overexpressed, potentially having activating mutations, and amplified in certain subsets of lung cancers. The ligand hepatocyte growth factor (HGF) can also be overexpressed in lung cancer or expressed in stroma, and both the MET receptor and the HGF ligand can be targets for therapeutics, especially in lung cancer. Activation of MET leads to a plethora of biochemical and biologic changes both in normal and cancerous cells. Preclinically, it has been shown that silencing or inactivating MET leads to decreased viability of cancer cells. There are a number of compounds against MET/HGF in clinical trials that have been shown to be active in lung cancers. This review will summarize the biology of MET as well as its therapeutic inhibition in lung cancer.

Fig 1.

Synergism between MET/recepteur d'origine nantais (RON) and epidermal growth factor receptor (EFGR). mTOR, mammalian target of rapamycin.

Fig 2.

Targeting of the hepatocyte growth factor (HGF)/MET pathway. HGF-dependent activation of the MET pathway can be disrupted through extracellular therapies that interfere with HGF binding to MET. Intracellular approaches can inhibit HGF-dependent and -independent mechanisms that lead to phosphorylation of MET kinase substrates.