Oncotarget

Research Papers:

Inhibition of pro-HGF activation by SRI31215, a novel approach to block oncogenic HGF/MET signaling

Benjamin Y. Owusu _, Namita Bansal, Phanindra K.M. Venukadasula, Larry J. Ross, Troy E. Messick, Sanjay Goel, Robert A. Galemmo and Lidija Klampfer

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Oncotarget. 2016; 7:29492-29506. https://doi.org/10.18632/oncotarget.8785

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Abstract

Benjamin Y. Owusu1, Namita Bansal2, Phanindra K.M. Venukadasula2, Larry J. Ross3, Troy E. Messick4, Sanjay Goel5, Robert A. Galemmo2, Lidija Klampfer1

1Department of Oncology, Drug Discovery Division, Southern Research, Birmingham, AL, USA

2Department of Chemistry, Drug Discovery Division, Southern Research, Birmingham, AL, USA

3High Throughput Screening, Southern Research, Drug Discovery Division, Birmingham, AL, USA

4The Wistar Institute, Southern Research, Philadelphia, PA, USA

5Albert Einstein Cancer Center, Southern Research, Bronx, NY, USA

Correspondence to:

Lidija Klampfer, e-mail: klampfer@southernresearch.org

Keywords: HGF, colon cancer, EGFR

Received: October 02, 2015    Accepted: March 28, 2016    Published: April 18, 2016

ABSTRACT

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.


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