Lysosomal Sequestration Impairs the Activity of the Preclinical FGFR Inhibitor PD173074.

Bernhard Englinger,Petra Heffeter,Julia Senkiv,Lisa Gabler,Walter Berger,Michael Grusch,Anna Laemmerer,Sebastian Kallus,Patrick Moser,Diana Groza,Christian Kowol

doi:10.3390/cells7120259

Abstract

Knowledge of intracellular pharmacokinetics of anticancer agents is imperative for understanding drug efficacy as well as intrinsic and acquired cellular resistance mechanisms. However, the factors driving subcellular drug distribution are complex and poorly understood. Here, we describe for the first time the intrinsic fluorescence properties of the fibroblast growth factor receptor inhibitor PD1703074 as well as utilization of this physicochemical feature to investigate intracellular accumulation and compartmentalization of this compound in human lung cancer cells. Cell-free PD173074 fluorescence, intracellular accumulation and distribution were investigated using analytical chemistry and molecular biology approaches. Analyses on a subcellular scale revealed selective drug accumulation in lysosomes. Coincubation with inhibitors of lysosomal acidification strongly enhanced PD173074-mediated fibroblast growth factor receptor (FGFR) inhibition and cytotoxicity. In conclusion, intrinsic fluorescence enables analysis of molecular factors influencing intracellular pharmacokinetics of PD173074. Lysosome-alkalinizing agents might represent candidates for rational combination treatment, preventing cancer cell-intrinsic PD173074 resistance based on lysosomal trapping.

Highlights

Clinical safety and efficacy are the two most important determinants for the successful development of pharmacological agents e.g., for cancer therapy
We initially aimed at characterizing the intrinsic fluorescence properties of PD173074 (Figure 1a)
In order to investigate the intracellular behavior of the drug, the FGFR1-amplified non-small cell lung cancer cell lines NCI-H1703 and NCI-H520 were used

Summary

Introduction

Clinical safety and efficacy are the two most important determinants for the successful development of pharmacological agents e.g., for cancer therapy. The pharmacokinetic and pharmacodynamic properties of novel compounds need to be carefully evaluated. Determination of parameters such as drug plasma half-life, organ distribution as well as metabolization is the basis for detailed (pre-)clinical characterization and successful application of cytotoxic chemotherapeutics as well as modern targeted anticancer agents. The behavior of such compounds within cancer cells is another important determinant of therapeutic efficacy and safety but is, in many cases, insufficiently understood. There is a need for more detailed knowledge on subcellular drug distribution in order to identify and combat intracellular factors limiting drug efficacy.

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Conclusion