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Role of HGF–MET Signaling in Primary and Acquired Resistance to Targeted Therapies in Cancer

Medical Oncology, Department of Experimental and Internal Medicine "F. Magrassi e A. Lanzara", Second University of Naples, Napoli 80131, Italy
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These authors contributed equally to this work.
Biomedicines 2014, 2(4), 345-358; https://doi.org/10.3390/biomedicines2040345
Received: 22 August 2014 / Revised: 11 November 2014 / Accepted: 17 November 2014 / Published: 25 November 2014
(This article belongs to the Special Issue New aspects of the Hepatocyte Growth Factor/c-Met System)
The Hepatocyte growth factor (HGF)—mesenchymal-epithelial transition (MET) pathway is deregulated in several cancers and is associated with aggressive phenotype and worse prognosis. MET, a tyrosine kinase receptor activated by HGF, plays a physiological role in embryogenesis, promoting cell growth, survival and motility. HGF–MET aberrant activation in tumorigenesis acts through various mechanisms: paracrine/autocrine HGF production, MET overexpression, MET germ-line and sporadic mutations and cross-talk with other growth factor receptors. In addition, MET activation could represent a mechanism of escape from other targeted therapies, through receptor amplification or over-stimulation by the ligand, as demonstrated in non-small cell lung cancer (NSCLC) and colorectal cancer (CRC) models with acquired resistance to epidermal growth factor receptor (EGFR) inhibitors and also in models of melanoma resistant to the BRAF inhibitor vemurafenib. As a consequence, a lot of molecules targeting MET signaling are under clinical investigation as single agent or in combination with other targeted drugs. Patient selection, based on MET expression on tumor samples (eventually, by re-biopsy of new metastatic sites), and pharmacokinetic/pharmacodynamic markers are needed. Authors review the latest data on the role of MET and the molecular mechanism underlying primary or acquired resistance to biological agents, focusing on NSCLC, CRC and melanoma. View Full-Text
Keywords: MET; primary and acquired resistance; targeted therapy MET; primary and acquired resistance; targeted therapy
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Della Corte, C.M.; Fasano, M.; Papaccio, F.; Ciardiello, F.; Morgillo, F. Role of HGF–MET Signaling in Primary and Acquired Resistance to Targeted Therapies in Cancer. Biomedicines 2014, 2, 345-358.

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