Journal Article

Efficacy of the highly selective focal adhesion kinase inhibitor BI 853520 in adenocarcinoma xenograft models is linked to a mesenchymal tumor phenotype

Hirt, Ulrich A, Haslinger, Christian, Garin-Chesa, Pilar, Sapountzis, Ioannis, Bader, Gerd, Schweifer, Norbert, Stadtmüller, Heinz, Braunger, Jürgen, Zoephel, Andreas, Bister, Bojan, Gerlach, Daniel, Adolf, Günther R, Kraut, Norbert, Baum, Anke, Waizenegger, Irene C, Weyer-Czernilofsky, Ulrike, Quant, Jens

2018

Overview

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.

• Publisher: Nature Publishing Group
• Subject: Adenocarcinoma / Animal models / Bioavailability / Biomarkers / Cancer / Cell adhesion & migration / Cell culture / Cell growth / Cell proliferation / Clinical trials / Drug therapy / E-cadherin / Enzyme inhibitors / Focal adhesion kinase / Gene set enrichment analysis / Genotype & phenotype / Immunodeficiency / Kinases / Mesenchyme / miRNA / Oral administration / Phenotypes / Prostate cancer / Prostate carcinoma / Protein-tyrosine kinase receptors / Xenografts