Abstract PO040: Protease inhibitors of HGF activation prevent HGF-dependent tumor progression and overcome resistance to anti-cancer therapy

Abstract

Abstract Overproduction of Hepatocyte Growth Factor (HGF) in the tumor microenvironment by tumor-associated fibroblasts or cancer cells is associated with poor patient outcomes and is a common cause of therapeutic resistance. HGF signals via the MET receptor, which results in the activation of downstream signaling pathways that promote cell survival, proliferation, migration, scattering, and invasion of cancer cells. HGF is secreted as an inactive precursor, pro-HGF, and proteolytic processing into its active form by one of the serine proteases, matriptase, hepsin, or HGF Activator (HGFA), is the rate-limiting step in HGF/MET signaling. The expression of these proteases is upregulated in cancer, whereas the activity of endogenous inhibitors of HGF-activating proteases, HGF-Activation Inhibitors (HAI-1/HAI-2), is reduced in cancer. We have developed small-molecule inhibitors of the three HGF-activating proteases, matriptase, hepsin, and HGFA. We refer to these inhibitors as synthetic HGF-Activation Inhibitors (sHAI), because they mimic the activity of HAI-1/HAI-2. The activity of sHAI was tested in in vitro models of therapeutic resistance and in in vivo models of HGF-driven lung cancer progression. ZFH7116 and VD2173, two lead SHAI compounds, are both potent inhibitors of the HGF-activating proteases and have good drug-like pharmacokinetic (PK) properties. We demonstrated that ZFH7116 and VD2173 inhibit proteolytic activation of pro-HGF to its active form. Both compounds overcome HGF-mediated resistance to EGFR and MET-targeted therapy in lung and colon cancer models of therapeutic resistance. Furthermore, ZFH7116 and VD2173 inhibit HGF-dependent growth of lung cancer cells in mice. Overall, our data demonstrate that inhibitors of HGF activation, such as ZFH7116 and VD2173, prevent HGF-dependent tumor growth, and overcome HGF-mediated resistance to targeted anti-cancer therapy. As such, they represent a unique way of inhibiting oncogenic HGF/MET signaling. Citation Format: Jorine J.L.P. Voss, Vishnu Damalanka, Matthew Mahoney, Lidija Klampfer, James W. Janetka. Protease inhibitors of HGF activation prevent HGF-dependent tumor progression and overcome resistance to anti-cancer therapy [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr PO040.