Targeting c-MET in gastrointestinal tumours: rationale, opportunities and challenges

Aberrant c-MET pathway activation occurs frequently in gastrointestinal tumours and can result from multiple mechanisms, including c-MET protein overexpression, MET amplification or enhanced transcription and/or aberrant autocrine or paracrine secretion of HGFActivated c-MET signalling results in enhanced cancer cell proliferation, survival and invasion; furthermore, a complex network of signalling involving other receptors enhances the potency and endurance of c-MET downstream signallingElevated c-MET expression/amplification has been associated with a poor clinical outcome in patients with gastro-oesophageal tumours, although conflicting reports exist with respect to a prognostic role of c-MET in colorectal cancerStructural studies of HGF and c-MET have yielded important results that paved the way for the development of anti-HGF and anti-c-MET monoclonal antibodies and specific or nonspecific c-MET tyrosine kinase inhibitorsIn contrast to the initial phase II studies, the phase III trials failed to show any clinical benefit from anti-HGF or anti-c-MET therapies in gastrointestinal tumours, even in patients with c-MET-positive diseaseAdditional biomarkers should be sought, using techniques such as MET RNA in situ hybridization (ISH) and MET single/double silver ISH and 'omics'-based approaches to identify patients that are likely to derive maximal benefits from anti-HGF/c-MET therapies