c-Met as a Target for Personalized Therapy

Abstract

MET and its ligand HGF are involved in many biological processes, both physiological and pathological, making this signaling pathway an attractive therapeutic target in oncology. Downstream signaling effects are transmitted via mitogen-activated protein kinase (MAPK), PI3K (phosphoinositide 3-kinase protein kinase B)/AKT, signal transducer and activator of transcription proteins (STAT), and nuclear factor-κB. The final output of the terminal effector components of these pathways is activation of cytoplasmic and nuclear processes leading to increases in cell proliferation, survival, mobilization and invasive capacity. In addition to its role as an oncogenic driver, increasing evidence implicates MET as a common mechanism of resistance to targeted therapies including EGFR and VEGFR inhibitors. In the present review, we summarize the current knowledge on the role of the HGF-MET signaling pathway in cancer and its therapeutic targeting (HGF activation inhibitors, HGF inhibitors, MET antagonists and selective/nonselective MET kinase inhibitors). Recent advances in understanding the role of this pathway in the resistance to current anticancer strategies used in lung, kidney and pancreatic cancer are discussed.

Keywords: HGF; MET; NSCLC; drug resistance; pancreatic cancer; renal cancer; targeted therapy.

Figure 1

Structure of the c-MET receptor. Extracellular portion include SEMA domain, PSI domain and IPT domain. Intracellular portion include juxtamembrane sequence, catalytic domain and C-terminal region with multifunctional docking site.

Figure 2

Structure of HGF. Its biologically active form consists of a disulfide-bond heterodimer containing an α-chain and a β-chain.

Figure 3

HGF-MET signaling pathway with its downstream effector components (MAPK, STAT, PI3K-AKT cascades and NF-κB) leading to increases in cell survival, motility and proliferation.

Figure 4

Therapeutic strategies targeting the HGF-MET signaling pathway in cancer include HGF activation inhibitors, HGF inhibitors, MET antagonists and MET kinase inhibitors.

Figure 5

Functional crosstalk of HGF-MET signaling pathway with EGFR and VEGFR signaling pathway. Notes: The anticancer treatment with EGFR antibodies (cetuximab, panitumumab) or EGFR TKIs (gefitinib, erlotinib) leads to MET amplification with subsequent activation of PI3K-AKT signaling. The resistance can be prevented by dual inhibition of EGFR and MET. Similarly, MET-HGF signaling pathway activation help evade VEGFR inhibition induced by bevacizumab, sunitinib or pazopanib and dual inhibition with VEGFR and MET inhibitor might overcome the resistance to anticancer treatment.