Targeting MET in cancer: rationale and progress

A Corrigendum to this article was published on 17 August 2012

This article has been updated

Key Points

  • The growth and motility factor hepatocyte growth factor/scatter factor (HGF/SF) and its receptor tyrosine kinase MET, the product of the MET proto-oncogene, provide essential signals for survival and long-distance migration of epithelial and myogenic precursor cells during embryogenesis. Cancer cells hijack HGF/SF–MET for invasion and metastasis, hence these molecules have emerged as key targets for cancer therapy.

  • Aberrant MET activation occurs in many types of cancer, and results from multiple mechanisms. Many carcinomas overexpress MET and the surrounding stroma overexpresses HGF/SF. Furthermore, certain patients with renal papillary, hepatocellular or gastric carcinomas carry point mutations in MET. These mutations have proved important in demonstrating a causal role of aberrant MET signalling in human cancer.

  • The intracellular signalling cascades activated by MET include the PI3K–AKT, RAC1–cell division control protein 42 (CDC42), RAP1 and RAS–MAPK pathways. An intricate network of cross-signalling involving the MET–epidermal growth factor receptor (EGFR), MET–vascular endothelial growth factor receptor (VEGFR) and MET–WNT pathways has also emerged in the past few years. This signalling network has major implications for therapy.

  • Structural studies of HGF/SF, the MET ectodomain and the pathways involved in activation of the precursor form of HGF/SF (pro-HGF/SF) have yielded important results and new opportunities for therapeutic intervention, namely specific inhibitors of the major HGF/SF activators, HGF/SF fragments with antagonistic activity — such as NK4 — and HGF/SF and MET antibodies.

  • Parallel efforts in the structural analysis of the MET kinase have led to extensive progress in the development of MET kinase inhibitors for cancer therapy, and three major classes of inhibitors have emerged from this work that differ in their binding mode, activity on MET kinase mutants and enzyme specificity.

  • A number of recent clinical trials have demonstrated strong activity of MET inhibitors in patients with a variety of advanced or metastatic tumours, including non-small-cell lung cancer (NSCLC), and breast, prostate, liver and renal cancer. MET inhibitors have also displayed clinical benefits in patients with NSCLC and patients with breast cancer who had developed resistance to EGFR therapy. These recent data clearly indicate that HGF/SF–MET therapeutics may have potential in several groups of cancer patients either alone or in combination with inhibitors of other signalling pathways.

Abstract

Uncontrolled cell survival, growth, angiogenesis and metastasis are essential hallmarks of cancer. Genetic and biochemical data have demonstrated that the growth and motility factor hepatocyte growth factor/scatter factor (HGF/SF) and its receptor, the tyrosine kinase MET, have a causal role in all of these processes, thus providing a strong rationale for targeting these molecules in cancer. Parallel progress in understanding the structure and function of HGF/SF, MET and associated signalling components has led to the successful development of blocking antibodies and a large number of small-molecule MET kinase inhibitors. In this Review, we discuss these advances, as well as results from recent clinical studies that demonstrate that inhibiting MET signalling in several types of solid human tumours has major therapeutic value.

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Figure 1: The multidomain structure of MET and HGF/SF.
Figure 2: Signalling pathways activated by HGF/SF and MET.
Figure 3: Cooperation between the HGF and WNT–β-catenin pathways.
Figure 4: Extracellular inhibitors of HGF/SF and MET.
Figure 5: MET kinase inhibitors.
Figure 6: Clinical trials with HGF/SF–MET inhibitors.

Change history

  • 17 August 2012

    In the legend to Figure 6c, the distribution according to therapeutic strategy (monotherapy versus combined therapy) involving HGF/SF–MET monotherapies should have read 44%.

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Acknowledgements

The authors would like to acknowledge J. Heuberger (MDC Berlin) for initial drawing of figures 2 and 3 and H. Niemann (University of Bielefeld) for critical reading of the manuscript. E.G. and W.B. acknowledge funding under the SFMET Project of the EU FP7 Programme and the generosity of the Jay and Betty Van Andel Foundation.

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Gherardi, E., Birchmeier, W., Birchmeier, C. et al. Targeting MET in cancer: rationale and progress. Nat Rev Cancer 12, 89–103 (2012). https://doi.org/10.1038/nrc3205

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