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  • Review Article
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Drug development of MET inhibitors: targeting oncogene addiction and expedience

Nature Reviews Drug Discovery volume 7, pages 504–516 (2008)Cite this article

Key Points

  • The MET oncogene encodes the tyrosine kinase receptor for hepatocyte growth factor (HGF), a widely distributed cytokine that is mainly involved in triggering invasive growth.

  • Invasive growth involves a complex genetic programme in which cell proliferation combines with cell–cell dissociation and movement, matrix degradation and survival. It occurs under physiological conditions — during organ development and regeneration, angiogenesis or wound healing — and in carcinoma progression, in which it drives tumour invasion and metastasis.

  • MET activity is deregulated in a vast number of human cancers owing to gene amplification, activating genetic mutations, transcriptional upregulation or the production of HGF-dependent autocrine circuits.

  • Several inhibitors targeting the HGF/MET system have been developed in recent years, including HGF and MET biological antagonists, anti-HGF and anti-MET antibodies, and small molecules. Some of them are now in Phase I and Phase II clinical trials.

  • In cultured cell lines, amplification of the MET gene correlates with drug sensitivity and MET inhibition leads to cell-cycle arrest or apoptosis. This indicates that MET amplification has been selected during neoplastic progression to sustain growth and survival of tumour cells and that cells with MET amplification are dependent on the continued activity of this oncogene for maintaining their transformed phenotype ('oncogene addiction'). This also suggests that human tumours featuring MET amplifications are likely to respond effectively to MET-targeted therapies.

  • The 'physiological' pro-invasive, anti-apoptotic and pro-angiogenic properties of MET can be exploited by tumour cells (already transformed by other means) to optimise their metastatic propensity ('oncogene expedience').

  • Targeted therapies against MET could be effective both as a front-line intervention to treat a limited subset of MET-addicted tumours and also as a secondary approach to limit the progression of a much wider spectrum of advanced cancers that use MET as an expedient for cancer dissemination.

Abstract

The MET tyrosine kinase stimulates cell scattering, invasion, protection from apoptosis and angiogenesis, thereby acting as a powerful expedient for cancer dissemination. MET can also be genetically selected for the long-term maintenance of the primary transformed phenotype, and some tumours appear to be dependent on (or 'addicted' to) sustained MET activity for their growth and survival. Because of its dual role as an adjuvant, pro-metastatic gene for some tumour types and as a necessary oncogene for others, MET is a versatile candidate for targeted therapeutic intervention. Here we discuss recent progress in the development of molecules that inhibit MET function and consider their application in a subset of human tumours that are potentially responsive to MET-targeted therapies.

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Figure 1: Schematic structure of HGF and MET.
Figure 2: MET-dependent signalling pathways.
Figure 3: Complex between the MET Sema domain and the HGF β-chain.
Figure 4: Structures of selected small-molecule MET inhibitors.

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Acknowledgements

We thank A. Bertotti and C. Boccaccio for discussion and critical reading of the manuscript; J. Hickman, M. Burbridge, T. Perera and S. Buchanan for providing informative material; and A. Cignetto for excellent secretarial assistance. Work from the authors' laboratory is supported by Associazione Italiana per la Ricerca sul Cancro, European Union Framework Programmes, Ministero dell'Università e della Ricerca, Compagnia di San Paolo and Fondazione CRT.

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  1. Division of Molecular Oncology, Institute for Cancer Research and Treatment (IRCC), University of Turin School of Medicine, Candiolo, 10060, Turin, Italy

    Paolo M. Comoglio, Silvia Giordano & Livio Trusolino

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  1. Paolo M. Comoglio
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  2. Silvia Giordano
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Correspondence to Paolo M. Comoglio or Livio Trusolino.

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P.M.C. received research support and/or consultation fees from AstraZeneca, Boehringer-Ingelheim, Johnson & Johnson, Merck and Servier.

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Comoglio, P., Giordano, S. & Trusolino, L. Drug development of MET inhibitors: targeting oncogene addiction and expedience. Nat Rev Drug Discov 7, 504–516 (2008). https://doi.org/10.1038/nrd2530

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