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Mechanisms of Resistance to Molecular Therapies Targeting the HGF/MET Axis

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Resistance to Anti-Cancer Therapeutics Targeting Receptor Tyrosine Kinases and Downstream Pathways

Part of the book series: Resistance to Targeted Anti-Cancer Therapeutics ((RTACT,volume 15))

  • 642 Accesses

Abstract

Targeted therapies by means of compounds that inhibit a specific target molecule represent a new perspective in the treatment of cancer. In contrast to conventional chemotherapy which acts mainly on dividing cells, targeted drugs allow to hit, in a more specific manner, subpopulations of cells directly involved in tumor progression. The frequent alteration of receptor tyrosine kinases (RTKs) in human malignancies led them to be considered as targets for anti-neoplastic therapies; this resulted in the development of several inhibitors that showed a strong clinical activity. The concept of “oncogene addiction” has added a further rationale to the use of targeted therapies. In general, targeted therapies induce tumor regression in a good percentage of patients who are selected to express the target of the drug. However, almost invariably, responsive patients develop resistance to the treatment and undergo tumor relapse. A challenge associated with targeted therapies is, therefore, to predict mechanisms that could cause resistance to the treatment and to find ways to circumvent these hurdles.

The tyrosine kinase receptor for the Hepatocyte Growth Factor (HGF), encoded by the MET gene, has recently become a very interesting and studied target. This review will summarize the role of this oncogene in human tumor development, the strategies employed to achieve its inhibition and the mechanisms of resistance to MET-targeted therapies.

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Abbreviations

EGFR:

Epidermal growth factor receptor

FDA:

Food and Drug Administration

FGFR2:

Fibroblast growth factor receptor 2

HCC:

Hepatocellular carcinoma

HGF:

Hepatocyte growth factor

mAb:

Monoclonal antibodies

MAPK:

Mitogen-activated protein kinase

MNNG:

Methylnitronitrosoguanidine

NSCLC:

Non-small-cell lung carcinoma

PI3K:

Phosphatidylinositide 3 kinase

RTK:

Receptor tyrosine kinase

SF-RON:

Short-form RON

TKI:

Tyrosine kinase inhibitor

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Authors and Affiliations

  1. Department of Oncology, University of Torino School of Medicine, Candiolo Cancer Institute-FPO IRCCS, Candiolo 10060, Torino, Italy

    Simona Corso & Silvia Giordano

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  1. Simona Corso
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  2. Silvia Giordano
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Correspondence to Silvia Giordano .

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  1. Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel

    Yosef Yarden

  2. Department of Microbiology, Immunology and Genetics, Ben-Gurion University of the Negev, Beer-Sheeva, Israel

    Moshe Elkabets

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Corso, S., Giordano, S. (2018). Mechanisms of Resistance to Molecular Therapies Targeting the HGF/MET Axis. In: Yarden, Y., Elkabets, M. (eds) Resistance to Anti-Cancer Therapeutics Targeting Receptor Tyrosine Kinases and Downstream Pathways. Resistance to Targeted Anti-Cancer Therapeutics, vol 15. Springer, Cham. https://doi.org/10.1007/978-3-319-67932-7_4

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