Notably, the HGF/MET axis also plays an important role in regulating tissue homeostasis and the inflammatory tissue response, as elucidated in preclinical models of degenerative diseases, including nephropathies and multiple sclerosis.30C32 In cancer, aberrant activation of the MET/HGF pathway, either through ligand-dependent or ligand-independent mechanisms, is a frequent event and has been described in Pyrimethamine several human malignancies, including NSCLC,33 glioma,34 and gastroesophageal,35,36 ovarian,37 breast,38 kidney,39 and liver cancer,40 strongly supporting the hypothesis that interfering with the MET/HGF pathway could represent a potential antitumor strategy. Several mechanisms are responsible for MET dysregulation, including protein overexpression, gene amplification, or gene mutation. gene copy number is a negative prognostic factor. In NSCLC, amplification of the gene is a relatively rare event, occurring in approximately 4% of patients not previously exposed to systemic therapies and in up to 20% of patients with acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors. In preclinical models, the presence of amplification is a predictor of high sensitivity to anti-MET compounds, and several agents have entered in clinical trials for patients having advanced disease, with promising results. The aim of the present review is to summarize available data on the role of MET in NSCLC and to describe therapeutic strategies under investigation. mutations, such as a deletion in exon 19 or an L858R substitution in exon 21, have demonstrated the superiority of gefitinib, erlotinib, and afatinib in terms of response rate and progression-free survival when compared with conventional platinum-based chemotherapy.8C14 Although no formal overall survival advantage has emerged from the aforementioned trials, mainly because of a drug crossover effect, median survival reached 2C3 years, indicating that EGFR tyrosine kinase inhibitors are changing the natural history of EGFR-mutated NSCLC.8C15 More recently, two studies, A8081001 and PROFILE 1007, established crizotinib as the best treatment for the small population of patients with ALK-translocated NSCLC.17,18 Unfortunately, often medicine is like Janus, the God with two faces, and the dark side in this context is represented by emergence of acquired resistance. Indeed, despite dramatic initial tumor regression, virtually all patients exposed to such targeted agents develop resistance after a median time of 10 months and inevitably progress and die from their disease. Amplification of the gene has been recognized as one of the most prominent mechanisms responsible for secondary resistance to EGFR tyrosine kinase inhibitors, and several sets of preclinical and clinical data indicate that coinhibition of MET and EGFR is a potentially effective strategy to overcome acquired resistance to these agents.20,21 Further, because of its central role in the proliferation and metastasis of cancer, has recently emerged as a potential tumor driver and is also a promising target in NSCLC.22 Here, we discuss the role of the mesenchymal-epidermal transition (MET) receptor, its abnormalities in cancer, and the clinical impact of anti-MET strategies in NSCLC. MET and NSCLC The gene encodes for the hepatocyte growth factor (HGF, also known as scatter factor) receptor, a transmembrane tyrosine kinase heterodimer protein involved in a complex signaling Pyrimethamine apparatus.23 HGF is produced particularly by stromal tissues and is also expressed in a broad spectrum of mesenchymal cells. Binding of HGF to the extracellular domain of the receptor determines autophosphorylation of the catalytic site and consequently activation of the downstream cascade in a domino-effect fashion (Figure 1).24,25 Open in a separate window Figure 1 Hepatic growth factor/mesenchymalCepidermal transition axis. Abbreviations: HGF, hepatic growth factor; mAbs, monoclonal antibodies; TKI, tyrosine kinase inhibitor; P13K, Phosphatidylinositide 3-kinase; MET, mesenchymalCepidermal transition. In physiological conditions, such as during embryogenesis or organogenesis,26C28 activation of the MET/HGF pathway regulates a wide network of signaling that leads to invasive growth, a phenomenon in which the cell gains the ability to move from its original niche toward the surrounding microenvironment, growing and improving proliferation and survival.29 This process becomes quiescent in adulthood, but different stressing conditions, such as angiogenesis or hypoxia, can lead to its reactivation. Notably, the HGF/MET axis also plays an important role in regulating tissue homeostasis and the inflammatory tissue response, as elucidated in preclinical models of degenerative diseases, including nephropathies and multiple sclerosis.30C32 In cancer, aberrant activation of the MET/HGF pathway, either through ligand-dependent or ligand-independent mechanisms, is a frequent event and has been described in several Pyrimethamine human malignancies, including NSCLC,33 glioma,34 and gastroesophageal,35,36 ovarian,37 breast,38 kidney,39 and liver cancer,40 strongly supporting the hypothesis that interfering with the MET/HGF pathway could represent a potential antitumor strategy. Several mechanisms are responsible for MET dysregulation, including protein overexpression, gene amplification, or gene mutation. Overexpression of MET is frequently observed in human cancer, including NSCLC, where this event is observed in 25%C75% of cases.41C43 In the absence of gene amplification, overexpression of MET could be related to transcriptional upregulation, and in some tumors the extent of expression has correlated with disease outcome and expansion.44C46 The current presence of a high amount of receptors for the cell surface causes receptor oligomerization, identifying an elevated sensibility to suboptimal ligand concentrations thus. gene amplification continues to be reported in various human being malignancies, including NSCLC, where this event can be reported in around 4% of instances.47 Several research show that an improved gene duplicate number can Rabbit polyclonal to ETFDH be an independent negative prognostic element in surgically resected NSCLC.47,48 In the scholarly research conducted by Okuda et al, a complete of.