HGF/c-MET: A Potential Target for the Treatment of Various Cancers
Authors: Anitha Kuttiappan , Dua Kamal , Chellappan Dinesh Kumar , Gupta Gaurav , Singh Sachin Kumar , Lakshmi Sabapathi Mohana , Bhatt Shvetank 
Published: February 2023

Background:

Cancer is the abnormal growth of cells in the body due to an imbalance in the
normal apoptotic pathways. The abnormality in the cancer cells makes them malignant. Various types of
treatment, including chemotherapy, radiation therapy, targeted therapy, and immunotherapy (IMT), are used
for cancer. Mesenchymal-epithelial transition factor (c-Met) belongs to the tyrosine kinase receptor family
and is overexpressed in various types of cancers. c-Met is a proto-oncogene and facilitates a wide range of
biological functions, including cell proliferation, growth, migration, invasion, and angiogenesis, through interaction
with its sole ligand hepatocyte growth factor (HGF). Currently, various c-mesenchymal-epithelial
transition (c-MET) inhibitors and antibodies are in human trials for their anti-cancer activity.

Introduction:

The c-MET is a kinase receptor for hepatocyte growth factor (HGF). It is wellrecognized
for its tumorigenic potential. HGF binding with c-Met leads to c-Met dimerization and c-
Met phosphorylation, which in turn activates many intracellular signalling pathways, including
ERK1/2, MAPK, STAT3, Rac1, and PI3K/AKT. These pathways regulate the proliferation, invasion,
and migration of cancer cells. Upon binding of HGF to c-MET, a series of phosphorylation reactions
get started, which leads to transcription and translation of various proteins, followed by abnormal
growth of cancerous tissues due to dysregulation of the cell cycle. The HGF/c-MET signalling pathways
have shown their potential in the development of many cancers, including gastric cancer (GC).
Several clinical trials have evaluated the therapeutic benefits of MET-targeted therapies involving various
agents, such as anti-MET antibodies, anti-HGF antibodies, and tyrosine kinase inhibitors (TKIs).
Various c-MET inhibitors are in clinical trials. The current review is focussed on the critical role of
the HGF/c-MET pathways in the progression of various cancers, including GC. In addition, this review
will also focus on the combination potential of c-MET inhibitors with immuno-oncology drugs,
such as programmed cell death protein 1 (PD-1) inhibitors, cytotoxic T-lymphocyte-associated antigen
4 (CTLA-4) inhibitors, tumor necrosis factor (TNF) receptor (OX-40) agonists, etc.

Materials and Methods:

The method adopted for the study was primarily based on the secondary
search through a systematic review of the literature.

Results:

A study of recent literature and various preclinical and human trials suggests the effectiveness
of c-MET inhibitors (alone or in combination) in different cancer types, including GC. In this paper,
the results have been elaborated as to how many papers/manuscripts/publications on the topic are
present, how many drugs are in Phase I/II/ III/RCT, etc., and that how many papers report on the clinical
outcomes of which agent/drug (mentioned in percentage).

Conclusion:

The use of c-MET inhibitors and antibodies has emerged as a latent therapeutic approach
for the treatment of various types of cancer. The c-MET inhibitors can also be used in combination
with various immunotherapeutic drugs, like PD-1 inhibitors, OX-40 agonists, etc.