Abstract Number: PB0729
Meeting: ISTH 2021 Congress
Background: The effect of hepsin levels on colorectal cancer has not been explored, despite of being associated with a worse prognosis in other tumors.
Aims: Here, for first time, we aimed to demonstrate the contribution of hepsin level to a worse prognosis in colorectal cancer and the prediction by virtual screening and identification of FDA-approved drugs as potential hepsin blockers.
Methods: In silico screening of 2037 compounds approved by the FDA was performed, and selected compounds were analyzed for their hepsin inhibition. The hepsin level effect was investigated on cell migration, invasion, proliferation and key cancer signaling pathways activation. The hepsin procoagulant function was determined by the thrombin generation assay. Hepsin levels were analyzed in plasma of resected and metastatic patients and mutant KRAS association was evaluated.
Results: Our results demonstrate that hepsin overexpression caused increased migration and invasion of Caco-2 cells. This overexpression resulted in higher phosphorylation of Erk1/2 and STAT3, associated with worse prognosis. In fact, our study showed a higher hepsin expression in metastatic patients, which was associated to mutant KRAS. The higher hepsin expression in Caco-2 cells also leaded to a higher thrombin generation in plasma, underlying a potential hypercoagulant state. Among the screened FDA-approved drugs, venetoclax showed the most potent effect as hepsin inhibitor and reduced the metastatic and prothrombotic phenotype of colorectal cancer cells.
Conclusions: Collectively, our results demonstrate that elevated hepsin levels may be indicative of a more aggressive and prothrombotic tumor phenotype and demonstrates an antitumor role of venetoclax as a hepsin inhibitor. This constitutes a foundation for molecular targeted therapy for colorectal cancer and other hepsin-overexpressing tumors.
To cite this abstract in AMA style:Rodenas-Bleda MC, Peñas-Martínez J, Zaragoza-Huesca D, Ortega-Sabater C, Peña-García J, Espín S, Ricote G, Ayala-de la Peña F, Luengo-Gil G, Nieto A, García-Molina F, Vicente V, Bernardi F, Pérez-Sánchez H, Carmona-Bayonas A, Martínez-Martínez I. Dual Effect of Hepsin Expression on Tumor Phenotype and Prothrombotic Potential of Colorectal Cancer Cells and Inhibition by Venetoclax [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/dual-effect-of-hepsin-expression-on-tumor-phenotype-and-prothrombotic-potential-of-colorectal-cancer-cells-and-inhibition-by-venetoclax/. Accessed August 19, 2022.
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