Role of HGF/MET axis in resistance of lung cancer to contemporary management

Kanwal Pratap Singh Raghav, Ana Maria Gonzalez-Angulo, George R. Blumenschein Jr


Lung cancer is the number one cause of cancer related mortality with over 1 million cancer
deaths worldwide. Numerous therapies have been developed for the treatment of lung cancer including
radiation, cytotoxic chemotherapy and targeted therapies. Histology, stage of presentation and molecular
aberrations are main determinants of prognosis and treatment strategy. Despite the advances that have
been made, overall prognosis for lung cancer patients remains dismal. Chemotherapy and/or targeted
therapy yield objective response rates of about 35% to 60% in advanced stage non-small cell lung cancer
(NSCLC). Even with good initial responses, median overall survival of is limited to about 12 months.
This reflects that current therapies are not universally effective and resistance develops quickly. Multiple
mechanisms of resistance have been proposed and the MET/HGF axis is a potential key contributor. The
proto-oncogene MET (mesenchymal-epithelial transition factor gene) and its ligand hepatocyte growth
factor (HGF) interact and activate downstream signaling via the mitogen-activated protein kinase (ERK/
MAPK) pathway and the phosphatidylinositol 3-kinase (PI3K/AKT) pathways that regulate gene expression
that promotes carcinogenesis. Aberrant MET/HGF signaling promotes emergence of an oncogenic
phenotype by promoting cellular proliferation, survival, migration, invasion and angiogenesis. The MET/
HGF axis has been implicated in various tumor types including lung cancers and is associated with adverse
clinicopathological profile and poor outcomes.

The MET/HGF axis plays a major role in development of radioresistance and chemoresistance to
platinums, taxanes, camtothecins and anthracyclines by inhibiting apoptosis via activation of PI3K-AKT
pathway. DNA damage from these agents induces MET and/or HGF expression. Another resistance
mechanism is inhibition of chemoradiation induced translocation of apoptosis-inducing factor (AIF) thereby
preventing apoptosis. Furthermore, this MET/HGF axis interacts with other oncogenic signaling pathways
such as the epidermal growth factor receptor (EGFR) pathway and the vascular endothelial growth factor
receptor (VEGFR) pathway. This functional cross-talk forms the basis for the role of MET/HGF axis in
resistance against anti-EGFR and anti-VEGF targeted therapies. MET and/or HGF overexpression from
gene amplification and activation are mechanisms of resistance to cetuximab and EGFR-TKIs. VEGF
inhibition promotes hypoxia induced transcriptional activation of MET proto-oncogene that promotes
angiogenesis and confers resistance to anti-angiogenic therapy. An extensive understanding of these
resistance mechanisms is essential to design combinations with enhanced cytotoxic effects.

Lung cancer treatment is challenging. Current therapies have limited efficacy due to primary and acquired
resistance. The MET/HGF axis plays a key role in development of this resistance. Combining MET/HGF
inhibitors with chemotherapy, radiotherapy and targeted therapy holds promise for improving outcomes.