Current advances of targeting HGF/c-Met pathway in gastric cancer

Abstract

Despite the advances in systemic chemotherapy, gastric adenocarcinoma (GC) remains the third most common cause of cancer-related deaths with poor prognosis. The heterogeneity of GC indicates that novel biomarkers should be established in order to further classify tumors and develop individual targeted therapies. High-quality preclinical and clinical research has demonstrated that growth factor (HGF)-hepatocyte growth factor receptor (c-Met) pathway plays a pivotal role on the growth, survival and invasiveness of GC. In particular, aberrant activation of HGF/c-Met signaling pathway has been associated with poor clinical outcomes, suggesting the therapeutic potential of c-Met. This has stimulated the development and evaluation of a number of c-Met targeted agents in an advance disease setting. In this review, we summarize the current state of the art in the advances on the inhibition of c-Met pathway, with particular emphasis on the clinical testing of c-Met targeted therapeutic agents. Furthermore, we discuss the challenges facing the incorporation of c-Met targeted agents in randomized trials, with the idea that the definition of the appropriate genetic and molecular context for the use of these agents remains the priority.

Comprehensive review of targeted therapy for colorectal cancer

“…[245][246][247][248] HGF is secreted mostly from mesenchymal tissues and is currently the only known ligand for MET. Its tissue and serum expression levels are related to poor prognosis of patients with different malignant tumors, such as breast, 249 esophageal, 250 and gastric cancers, 251 and especially CRC. Patients with advanced CRC have elevated serum HGF at diagnosis and decreased levels after cancer resection.…”

<p><em>MET</em> Inhibitors for the Treatment of Gastric Cancer: What’s Their Potential?</p>

“…It can occur by protein overexpression, gene amplification, increased HGF ligand autocrine expression, enhanced paracrine ligand-mediated stimulation, inadequate c-MET degradation, ligand-independent activation and rarely gene mutation, 19 in addition to the role of environmental conditions such as inflammation and hypoxia. 24 The most common mechanism of MET pathway abnormal activation in GC is via protein overexpression with resultant excessive kinase activation. MET protein expression on immunohistochemistry (IHC) is predominantly detected in 50-65% of GC.…”

RevisitingMET: Clinical Characteristics and Treatment Outcomes of Patients with Locally Advanced or Metastatic,MET-Amplified Esophagogastric Cancers

“…Therapeutically exploiting molecular biomarkers, including MET , in EGC has been plagued by multiple barriers, among the most important of which is tumoral heterogeneity. Despite, encouraging phase II studies of c‐MET antibodies (rilotumumab, onartuzumab), larger phase III EGC studies using the same screening criteria for c‐MET positivity revealed no survival benefits, regardless of c‐MET staining [46]. Larger efforts to assess for concordance between tissue (including both primary and metastatic sites) and blood (circulating tumor DNA) in order to evaluate the effect of tumor heterogeneity on response, as well as the impact of other molecular features, such as the presence of RTK co‐amplification, may aid in refining the population who are most likely to benefit from MET‐directed therapies, either alone or in combination.…”