Efficacy of the highly selective focal adhesion kinase inhibitor BI 853520 in adenocarcinoma xenograft models is linked to a mesenchymal tumor phenotype
| Autor: | Norbert Schweifer, Norbert Kraut, Gerd Bader, Sapountzis Ioannis, Jürgen Braunger, Irene Waizenegger, Anke Baum, Günther R. Adolf, Ulrich Hirt, Jens Quant, Daniel Gerlach, Bojan Bister, Heinz Stadtmüller, Andreas Zoephel, Ulrike Weyer-Czernilofsky, Christian Haslinger, Pilar Garin-Chesa |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Volume of distribution Cancer Research Chemistry Autophosphorylation lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens medicine.disease lcsh:RC254-282 Article In vitro Focal adhesion 03 medical and health sciences 030104 developmental biology 0302 clinical medicine 030220 oncology & carcinogenesis medicine Cancer research Adenocarcinoma Potency Molecular Biology IC50 Tyrosine kinase |
| Zdroj: | Oncogenesis Oncogenesis, Vol 7, Iss 2, Pp 1-11 (2018) |
| ISSN: | 2157-9024 |
| DOI: | 10.1038/s41389-018-0032-z |
| Popis: | Focal adhesion kinase (FAK), a non-receptor tyrosine kinase, has attracted interest as a target for pharmacological intervention in malignant diseases. Here, we describe BI 853520, a novel ATP-competitive inhibitor distinguished by high potency and selectivity. In vitro, the compound inhibits FAK autophosphorylation in PC-3 prostate carcinoma cells with an IC50 of 1 nmol/L and blocks anchorage-independent proliferation of PC-3 cells with an EC50 of 3 nmol/L, whereas cells grown in conventional surface culture are 1000-fold less sensitive. In mice, the compound shows long half-life, high volume of distribution and high oral bioavailability; oral dosing of immunodeficient mice bearing subcutaneous PC-3 prostate adenocarcinoma xenografts resulted in rapid, long-lasting repression of FAK autophosphorylation in tumor tissue. Daily oral administration of BI 853520 to nude mice at doses of 50 mg/kg was well tolerated for prolonged periods of time. In a diverse panel of 16 subcutaneous adenocarcinoma xenograft models in nude mice, drug treatment resulted in a broad spectrum of outcomes, ranging from group median tumor growth inhibition values >100% and tumor regression in subsets of animals to complete lack of sensitivity. Biomarker analysis indicated that high sensitivity is linked to a mesenchymal tumor phenotype, initially defined by loss of E-cadherin expression and subsequently substantiated by gene set enrichment analysis. Further, we obtained microRNA expression profiles for 13 models and observed that hsa-miR-200c-3p expression is strongly correlated with efficacy (R2 = 0.889). BI 853520 is undergoing evaluation in early clinical trials. |
| Databáze: | OpenAIRE |
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