MET inhibition in lung cancer Full Text
Translational Lung Cancer Research,  Review Article

Menis J. et al .– This paper aims to summarize data on Met biological function, on its interaction with cell signaling and other pathways and to present data on those Met inhibitors currently under evaluation. The discovery of new cancer–driver genes and the enforcement of molecules targeting them have changed the landscape of Non Small Cell Lung Cancer (NSCLC) treatment.As a matter of fact, the previous scenario of advanced NSCLC treatment has been completely revolutionized, switching from a “one size fits all” approach to a personalized therapy. It was concluded that Met can act as an ‘oncogene expedient’ even in absence of genetic alterations and might potentiate the effect of other oncogenes, promote malignant progression and participate in tumor angiogenesis. Met dysregulation correlates with disease prognosis in numerous cancers and represents a possible target for personalized treatment. The clinical efficacy of Met targeting agents in lung cancer needs further details from the ongoing trials as well as more information are necessary to establish the most appropriate diagnostic test to identify Met expression or amplification.

  • Met is a heterodimer receptor tyrosine kinase composed of a ?–chain and a ?–chain, linked by a disulphide bond.
  • Met was originally isolated as the product of a human oncogene, trp–met, in tumor cells treated with a chemical carcinogen.
  • Met gene encodes a 170–kD protein (p170met) that has constitutive and ligand–independent tyrosin–kinase activity.
  • Met has pivotal functions in embryogenesis and organogenesis of placenta, liver, kidney, neurons and muscles.
  • Moreover, in vivo, Met receptor activation determines a phenomenon called “invasive growth”, which includes cell proliferation, scattering, survival, motility and invasion, epithelial–mesenchymal transition and branched morphogenesis
  • In this scenario Met, a heterodimere receptor tyrosine kinase deeply involved into embryogenesis and organogenesis, has been introduced many years ago as a potential target for biological agents, becoming“druggable” only in this last period of time.
  • Met can be altered through receptor overexpression, genomic amplification, mutations or alternative splicing, autocrine or paracrine secretion of hepatic growth factor (HGF): these dysregulations stimulate tumorigenesis (in terms of cell–cell detachment, proliferation, invasion, angiogenesis and survival) and metastatization.
  • Met is overexpressed in lung cancer and Met gene amplification can drive the dependency of cell survival and proliferation upon the Met signaling. Both Met overexpression and amplification seem to correlate with poor prognosis.
  • Met amplification is also described to be linked to EGFR acquired resistance.
  • Several Met inhibitors have been tested both in preclinical and human trials, demonstrating activity in lung cancer treatment.
  • In patients with advanced NSCLC, a correct definition of the histotype is still the first step to design a proper therapeutic algorithm, but personalized molecular diagnosis is becoming more and more relevant.
  • Several molecules are currently under investigation and two of them already reached phase III trials in advanced NSCLC.

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