Sri31215, A Novel Inhibitor Of Oncogenic Hgf/Met Signaling

Constitutive activation of MET signaling, frequently observed in cancer, triggers signaling by AKT, ERK 1/2 and STAT3, and promotes survival, proliferation, migration and invasion of cancer cells. Accordingly, MET amplification or overexpression of its ligand, hepatocyte growth factor (HGF), are associated with tumor aggressiveness, resistance to therapy and poor prognosis in many cancer patients. Cancer cells can secrete HGF which triggers autocrine HGF/MET signaling, however, fibroblasts are the predominant source of HGF and activate MET expressed on tumor cells in a paracrine manner. Cancer cells and fibroblasts secrete HGF as an inactive precursor, pro-HGF. A crucial step in the regulation of HGF/MET signaling is the proteolytic processing of the inactive precursor, pro-HGF, to its active form by one of the three serine proteases, matriptase, hepsin or HGF activator (HGFA). This is the rate-limiting step in the HGF/MET signaling pathway, controlled by the inhibitors of HGF activation, hepatocyte growth factor activator inhibitors 1 and 2 (HAI-1/2). We synthesized a novel small molecule, SRI31215, a triplex inhibitor of matriptase, hepsin and HGFA, mimicking the biological activity of HA1-1/2. We confirmed that SRI31215 inhibits the proteolytic activation of pro-HGF and blocks HGF-induced MET activation and signaling by AKT, ERK 1/2 and STAT3. SRI31215 blocked fibroblast-induced epithelial-to-mesenchymal transition (EMT) and prevented scattering and migration of cancer cells. Finally, we demonstrated that SRI31215 sensitized HGF-producing colon cancer cells to epidermal growth factor receptor inhibitors (EGFRi) and inhibited fibroblast-mediated, HGF-dependent, resistance to EGFRi in colon cancer. Thus, SRI31215 blocks signaling between cancer cells and fibroblasts and inhibits the tumor-promoting activity of cancer associated fibroblasts. Taken together, our data demonstrate that inhibitors of HGF activation, such as SRI31215, represent a novel approach to curb the growth and metastatic spread of tumor cells that are addicted to HGF/MET signaling and to overcome primary and acquired resistance to EGFR-targeted therapy. Citation Format: Benjamin Y. Owusu, Phanindra K. Venukadasula, Robert A. Galemmo, Lidija Klampfer. SRI31215, a novel inhibitor of oncogenic HGF/MET signaling. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1583.