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Lysosomal Sequestration Impairs the Activity of the Preclinical FGFR Inhibitor PD173074

Bernhard Englinger1, Sebastian Kallus2,3, Julia Senkiv4,5

  • 1Institute of Cancer Research and Comprehensive Cancer Center, Department of Medicine I, Medical University of Vienna, A-1090 Vienna, Austria. bernhard.englinger@meduniwien.ac.at.

Cells
|December 15, 2018
PubMed

Insights

This study reveals that the anticancer drug PD1703074 accumulates in lysosomes, reducing its efficacy. Combining it with lysosome-alkalinizing agents may overcome drug resistance in cancer cells.

Area of Science:

  • Pharmacology
  • Cell Biology
  • Oncology

Background:

  • Intracellular pharmacokinetics are crucial for anticancer drug efficacy and resistance.
  • Subcellular drug distribution factors are complex and not well understood.
  • Investigating drug distribution aids in developing effective cancer therapies.

Purpose of the Study:

  • To characterize the intrinsic fluorescence of PD1703074, a fibroblast growth factor receptor inhibitor.
  • To investigate the intracellular accumulation and compartmentalization of PD1703074 in human lung cancer cells.
  • To explore the potential of lysosome-alkalinizing agents in overcoming drug resistance.

Main Methods:

  • Utilized intrinsic fluorescence properties of PD1703074 for analysis.
  • Employed analytical chemistry and molecular biology techniques.
  • Performed subcellular-scale analyses to determine drug distribution.

Main Results:

  • PD1703074 exhibits intrinsic fluorescence, enabling its tracking within cells.
  • Selective accumulation of PD1703074 was observed in lysosomes.
  • Inhibiting lysosomal acidification enhanced PD1703074's anti-cancer effects and cytotoxicity.

Conclusions:

  • Intrinsic fluorescence is a valuable tool for studying intracellular pharmacokinetics of PD1703074.
  • Lysosomal trapping contributes to cellular resistance against PD1703074.
  • Lysosome-alkalinizing agents show promise for combination therapy to enhance PD1703074 efficacy.
Keywords:
TKIcancerdrug sequestrationfibroblast growth factor receptorfluorescencelysosomes

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