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MET-dependent solid tumours — molecular diagnosis and targeted therapy

Abstract

Attempts to develop MET-targeted therapies have historically focused on MET-expressing cancers, with limited success. Thus, MET expression in the absence of a genomic marker of MET dependence is a poor predictor of benefit from MET-targeted therapy. However, owing to the development of more sensitive methods of detecting genomic alterations, high-level MET amplification and activating MET mutations or fusions are all now known to be drivers of oncogenesis. MET mutations include those affecting the kinase or extracellular domains and those that result in exon 14 skipping. The activity of MET tyrosine kinase inhibitors varies by MET alteration category. The likelihood of benefit from MET-targeted therapies increases with increasing levels of MET amplification, although no consensus exists on the optimal diagnostic cut-off point for MET copy number gains identified using fluorescence in situ hybridization and, in particular, next-generation sequencing. Several agents targeting exon 14 skipping alterations are currently in clinical development, with promising data available from early-phase trials. By contrast, the therapeutic implications of MET fusions remain underexplored. Here we summarize and evaluate the utility of various diagnostic techniques and the roles of different classes of MET-targeted therapies in cancers with MET amplification, mutation and fusion, and MET overexpression.

Key points

  • The degree of MET amplification is a continuous variable that can be measured using fluorescence in situ hybridization or next-generation sequencing. No consensus exists on the most appropriate diagnostic cut-off point for MET amplification.

  • Patients with solid tumours harbouring high-level MET amplifications have a greater likelihood of benefit from single-agent or combination MET-targeted therapies than those with lower MET copy number gains.

  • MET mutations are highly heterogeneous and can range from those that involve the MET kinase domain to those that result in MET exon 14 skipping.

  • The activity of type I or type II MET tyrosine kinase inhibitors can substantially differ by MET mutation type.

  • A wide variety of MET fusions have been identified, although the biology of these alterations and their implications for responses to MET-targeted therapies are not well characterized.

  • MET overexpression in the absence of a known driver of MET dependence is a poor predictor of benefit from MET-targeted therapies.

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Fig. 1: Diagnosis of MET-amplified cancer.
Fig. 2: Targeted therapies and response rates in patients with MET-amplified cancers.
Fig. 3: MET mutations.
Fig. 4: MET fusions.

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Acknowledgements

The authors are grateful to C. Wilhelm of Memorial Sloan Kettering Cancer Center for his thorough review and assistance with the manuscript. Some of the results shown here are in whole or part based upon data generated by the TCGA Research Network: https://www.cancer.gov/tcga.

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Correspondence to Alexander Drilon.

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R.G., J.L., J.C. and N.R. declare no competing interests. M.A. has received honoraria/speaker fees from Biocartis and Invivoscribe relating to activities outside the submitted work. A.D. has received honoraria/speaker fees from Abbvie, AstraZeneca, Beigene, BergenBio, Blueprint Medicines, Exelixis, Hengrui Therapeutics, Helsinn, Ignyta/Genentech/Roche, Lilly, Loxo, Loxo/Bayer/Lilly, Medscape, MORE Health, OncLive, PeerVoice, Pfizer, Physicians Education Resources, Research to Practice, Takeda/Ariad/Millennium, Targeted Oncology, TP Therapeutics, Tyra Biosciences, Verastem and Wolters Kluwer; has served on/received fees for membership of the advisory board of Abbvie, AstraZeneca, Beigene, BergenBio, Blueprint Medicines, Exelixis, Hengrui Therapeutics, Helsinn, Ignyta/Genentech/Roche, Loxo, Loxo/Bayer/Lilly, MORE Health, Pfizer, Takeda/Ariad/Millennium, TP Therapeutics, Tyra Biosciences and Verastem; has received research funding from Exelixis, Foundation Medicine, GlaxoSmithKline, Ignyta/Roche, Pfizer, PharmaMar, Taiho and Teva; and has received non-financial support from Ignyta/Roche, Merck and Puma.

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Guo, R., Luo, J., Chang, J. et al. MET-dependent solid tumours — molecular diagnosis and targeted therapy. Nat Rev Clin Oncol 17, 569–587 (2020). https://doi.org/10.1038/s41571-020-0377-z

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