The binding of
hepatocyte growth factor (HGF) to its receptor MET activates a signaling cascade that promotes cell survival, proliferation, cell scattering, migration and invasion of malignant cells. HGF is secreted by
cancer cells or by tumor-associated fibroblasts as
pro-HGF, an inactive precursor. A key step in the regulation of HGF/MET signaling is proteolytic processing of
pro-HGF to its active form by one of the three
serine proteases,
matriptase,
hepsin or
HGF activator (HGFA).We developed
SRI 31215, a small molecule that acts as a triplex inhibitor of
matriptase,
hepsin and HGFA and mimics the activity of HAI-1/2, endogenous inhibitors of HGF activation. We demonstrated that
SRI 31215 inhibits fibroblast-induced MET activation, epithelial-mesenchymal transition and migration of
cancer cells.
SRI 31215 overcomes primary resistance to
cetuximab and
gefitinib in HGF-producing
colon cancer cells and prevents fibroblast-mediated resistance to EGFR inhibitors. Thus,
SRI 31215 blocks signaling between
cancer cells and fibroblasts and inhibits the
tumor-promoting activity of cancer-associated fibroblasts.Aberrant HGF/MET signaling supports cell survival, proliferation, angiogenesis, invasion and metastatic spread of
cancer cells, establishing HGF and MET as valid therapeutic targets. Our data demonstrate that inhibitors of HGF activation, such as
SRI 31215, merit investigation as potential
therapeutics in
tumors that are addicted to HGF/MET signaling. The findings reported here also indicate that inhibitors of HGF activation overcome primary and acquired resistance to anti-EGFR
therapy, providing a rationale for concurrent inhibition of EGFR and HGF to prevent therapeutic resistance and to improve the outcome of
cancer patients.