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

ABSTRACT: 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.

SUBMITTER: Hirt UA

PROVIDER: S-EPMC5833389 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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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 UA Waizenegger Irene C IC Schweifer Norbert N Haslinger Christian C Gerlach Daniel D Braunger Jürgen J Weyer-Czernilofsky Ulrike U Stadtmüller Heinz H Sapountzis Ioannis I Bader Gerd G Zoephel Andreas A Bister Bojan B Baum Anke A Quant Jens J Kraut Norbert N Garin-Chesa Pilar P Adolf Günther R GR

Oncogenesis 20180223 2

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 IC<sub>50</sub> of 1 nmol/L and blocks anchorage-independent proliferation of PC-3 cells with an EC<sub>50</sub> of 3 nmol/L, whereas cells g ...[more]

PMID: 29472531

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Project description:BACKGROUND:BI 853520 is a potent inhibitor of focal adhesion kinase and is currently under clinical development for the treatment of non-hematological malignancies. OBJECTIVE:The objective of this study was to evaluate the effect of food and liquid dispersion on the pharmacokinetics of BI 853520 in two open-label, crossover substudies. PATIENTS AND METHODS:Sixteen patients with advanced solid tumors were enrolled in each substudy. The order of administration was randomized, and pharmacokinetic samples were collected for 48 h after administration of a 200 mg dose of BI 853520. Lack of effect would be demonstrated if the 90% confidence interval (CI) of the ratio of the adjusted geometric mean (GMR) of the area under the plasma curve (area under the plasma concentration-time curve from time zero to the last quantifiable concentration at tz [[Formula: see text]] and observed area under the plasma concentration-time curve extrapolated from time zero to infinity [AUC0-?,obs]) and maximum plasma concentration (Cmax) did not cross the 80-125% (bioequivalence) boundaries. RESULTS:Adjusted GMRs (90% CIs) for the fed versus fasted state were 92.46% (74.24-115.16), 98.17% (78.53-122.74), and 87.34% (71.04-107.38) for [Formula: see text], AUC0-?,obs, and Cmax, respectively. Although the 90% CIs were not within bioequivalence limits for the food-effect study, the limited reductions in these pharmacokinetic parameters after administration with a high-fat meal are unlikely to be clinically relevant. Compared with a tablet, administration of BI 853520 as a liquid dispersion did not strongly affect [Formula: see text], AUC0-?,obs, or Cmax, resulting in adjusted GMRs (90% CIs) of 1.00 (0.92-1.09), 0.98 (0.90-1.07), and 0.93 (0.86-1.01), respectively. CONCLUSIONS:These studies demonstrate that BI 853520 can be given with no food restrictions, and as a liquid dispersion, without strongly impacting pharmacokinetics. These pharmacokinetic properties may help make BI 853520 dosing more convenient and flexible, improving treatment compliance. CLINICAL TRIALS REGISTRATION:ClinicalTrials.gov identifier: NCT01335269.

Dataset Information

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

Publications

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

Similar Datasets

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