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When the MET receptor kicks in to resist targeted therapies

Oncogene volume 40, pages 4061–4078 (2021)Cite this article

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Abstract

Although targeted therapies have increased the life expectancy of patients with druggable molecular alterations directly involved in tumor development, the efficacy of these therapies is limited by acquired resistances leading to treatment failure. Most targeted therapies, including ones exploiting therapeutic antibodies and kinase inhibitors, are directed against receptor tyrosine kinases (RTKs) or major signaling hubs. Resistances to these therapies arise when inhibition of these targets is bypassed through activation of alternative signaling pathways. In recent years, activation of the receptor tyrosine kinase MET has been shown to promote resistance to various targeted therapies. This casts MET as important actor in resistance. In this review, we describe how the MET receptor triggers resistance to targeted therapies against RTKs such as EGFR, VEGFR, and HER2 and against signaling hubs such as BRAF. We also describe how MET can be its own resistance factor, as illustrated by on-target resistance of lung tumors harboring activating mutations causing MET exon 14 skipping. Interestingly, investigation of all these situations reveals functional physiological relationships between MET and the target of the therapy to which the cancer becomes resistant, suggesting that resistance stems from preexisting mechanisms. Identification of MET as a resistance factor opens the way to co-treatment strategies that are being tested in current clinical trials.

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Fig. 1: Resistance mechanisms involving the MET receptor and main therapeutic strategies.
Fig. 2: On-target resistance to MET TKIs in NSCLC displaying MET exon 14 skipping.
Fig. 3: Flowchart for potential sequential treatments of METex14 lung cancer patients.
Fig. 4: Off- and on-target resistances involving the MET receptor.

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Acknowledgements

This work was supported by the CNRS, the Institut Pasteur de Lille, and INSERM, and by grants from the “Cancéropôle Nord-Ouest”, the “Ligue Contre le Cancer, Comités Nord et Aisne”, the “Agence nationale de la recherche” and the “Institut National du Cancer”.

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  1. CNRS, Inserm, Institut Pasteur de Lille, CHU Lille, UMR9020-U1277—CANTHER—Cancer Heterogeneity Plasticity and Resistance to Therapies, Univ. Lille, Lille, France

    Marie Fernandes, Philippe Jamme, Alexis B. Cortot, Zoulika Kherrouche & David Tulasne

  2. Thoracic Oncology Department, CHU, Univ. Lille, Lille, France

    Alexis B. Cortot

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  1. Marie Fernandes
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Fernandes, M., Jamme, P., Cortot, A.B. et al. When the MET receptor kicks in to resist targeted therapies. Oncogene 40, 4061–4078 (2021). https://doi.org/10.1038/s41388-021-01835-0

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