Targeting the hepatocyte growth factor/mesenchymal epithelial transition pathway in gastric cancer: biological rationale and clinical applications

Abstract

Advanced gastric cancer (GC) is a dreadful disease with a poor prognosis and the majority of patients die within 1 year of diagnosis. In the past decade, important signaling pathways promoting tumor proliferation and aggressiveness have been evaluated; the hepatocyte growth factor/mesenchymal epithelial transition (MET) pathway is one of the most promising pathways in that regard. This pathway has been evaluated in preclinical and early clinical settings of GC. From the very early studies, MET expression has been recognized as an important poor prognostic marker in GC. However, only after the development of MET-targeting agents, it became important in terms of antitumor therapy with the clinical evaluation of several MET-targeting agents in GC. The results of the ongoing multicenter studies evaluating MET-targeting agents are eagerly awaited as they may improve our understanding of the precise role of these agents in the treatment armamentarium of advanced GC.

Keywords:

• gastric cancer
• HGF
• MET
• systemic treatment
• targeted therapy

Financial & competing interests disclosure

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Gastric cancer (GC) is a major health problem, ranking fourth in incidence and second in mortality among all cancers worldwide.

• Advanced (unresectable or metastatic) GC is a dreadful disease with a poor prognosis and the majority of patients die within 1 year of diagnosis.

• Abnormal mesenchymal epithelial transition (MET) pathway signaling is a characteristic of many cancer types, and may occur through gene amplification or protein overexpression, which interrupts regulatory feedback mechanisms.

• The vast majority of the available data suggest a poor prognostic value of MET gene amplification and/or overexpression in both early and advanced GC.

• Multiple compounds targeting HGF/MET pathway have been developed. These include both monoclonal antibodies targeting the receptor and ligand, and small-molecule TKIs targeting the intracellular parts of the receptor.

• Numerous preclinical studies have shown significant activity for MET-targeting agents in GC cell lines as well as xenograft models.

• Plenty of Phase II studies for MET-targeting tyrosine kinase inhibitors and monoclonal antibodies have been published with very encouraging results.

• A number of Phase II and III studies are ongoing in different regions of the world evaluating innovative use of MET-targeting therapeutics in advanced gastric/gastroesophageal carcinoma.

• The results of these studies, expected within the next 4 years, may change our approach to MET-targeting therapeutics in the treatment armamentarium of GC.