MET Signaling Pathway: A Rational Target for Cancer Therapy

In Journal of Clinical Oncology (JCO), two groups of investigators provide important evidence for the critical role of MET in malignant transformation. Graziano et al report a dose-proportional risk of recurrence and decreased survival associated with increasing MET gene copy number in stages II to III gastric adenocarcinoma. Lennerz et al show that MET amplification in gastroesophogeal carcinomas is uncommon, observed in only 2% of their patient cohort. However, an increase in MET gene copy number was associated with higher presenting tumor stage and grade as well as shorter median survival. These two reports add to a growing body of evidence that MET is a key driver of oncogenic transformation in a defined subset of cancers. This Understanding the Pathway article will provide an overview of the MET signaling pathway, discuss the role of MET in malignancy, and consider the potential for targeting MET in cancer therapy. MET is an integral plasma membrane protein that relays signals from the extracellular environment into the cytoplasm (Fig 1). MET is activated when its extracellular domain binds to hepatocyte growth factor (HGF), also known as scatter factor. This protein is primarily expressed on epithelial cells, whereas HGF is secreted by mesenchymal cells and bound in an inactive form to heparin proteoglycans within the extracellular matrix. The HGF polypeptide is inactive in its initial form and must be cleaved into a disulfide-linked heterodimer by an extracellular protease—HGF activator—to acquire MET-binding activity. HGF activator is a serine protease that is produced in the liver but localized and activated selectively at sites of tissue injury and in cancer. The mesenchymal-epithelial communication mediated by HGF-MET signaling is critical to the formation of threedimensional body structures (morphognesis) through cellular behaviors collectively described as invasive growth: proliferation and survival (resistance to apoptotic signals), increased cell motility, cell dissociation (scattering), epithelial tubulogenesis, infiltration of tissues, and stimulation of angiogenesis. These MET-dependent behaviors are essential for normal processes such as embryogenesis, organ regeneration, and wound healing. Cancers with increased MET activity commandeer this machinery to facilitate tumor growth and invasion/metastasis. The cascade of molecular events triggered by HGF begins with MET kinase activation within the receptor’s cytoplasmic tail. Two tyrosine residues within the kinase domain undergo transautophosphorylation to create a fully activated enzyme. Two additional tyrosine residues are subsequently phosphorylated, resulting in a high-affinity binding motif that recruits a range of Src homology 2 domain– containing proteins, which include nonenzymatic adaptor proteins such as growth factor receptor– bound protein 2 (GRB2) and GRB2-associated binding protein 1. GRB2-associated binding protein 1 is phosphorylated by MET and cooperates with GRB2 and other adaptors to serve as a scaffold for additional signaling proteins, including phosphoinositide 3-kinase, phospholipaseC1, STAT3, focal adhesion kinase (involved in motility), and the tyrosine MET