Inhibition of pro-HGF activation by SRI31215, a novel approach to block oncogenic HGF/MET signaling.
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.
Department of Oncology, Drug Discovery Division, Southern Research, Birmingham, AL, USA.
Benjamin Y
BY
Owusu
Department of Chemistry, Drug Discovery Division, Southern Research, Birmingham, AL, USA.
Namita
N
Bansal
Department of Chemistry, Drug Discovery Division, Southern Research, Birmingham, AL, USA.
Phanindra K M
PK
Venukadasula
High Throughput Screening, Southern Research, Drug Discovery Division, Birmingham, AL, USA.
Larry J
LJ
Ross
The Wistar Institute, Southern Research, Philadelphia, PA, USA.
Troy E
TE
Messick
Albert Einstein Cancer Center, Southern Research, Bronx, NY, USA.
Sanjay
S
Goel
Department of Chemistry, Drug Discovery Division, Southern Research, Birmingham, AL, USA.
Robert A
RA
Galemmo
Department of Oncology, Drug Discovery Division, Southern Research, Birmingham, AL, USA.
Lidija
L
Klampfer
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001550:Benzamidines / Q000494:pharmacology*; D000072645:Cancer-Associated Fibroblasts / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D017228:Hepatocyte Growth Factor / Q000037:antagonists & inhibitors*; D006801:Humans; D011498:Protein Precursors / Q000037:antagonists & inhibitors* / Q000187:drug effects; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors*; D011744:Pyrimidinones / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*
D000970:Antineoplastic Agents; D001550:Benzamidines; C066855:HGF protein, human; D011498:Protein Precursors; D011744:Pyrimidinones; C000625563:SRI 31215; C086013:pro-hepatocyte growth factor; D017228:Hepatocyte Growth Factor; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met
EGFR; HGF; colon cancer