Lipid droplet-mediated scavenging as novel intrinsic and adaptive resistance factor against the multikinase inhibitor ponatinib

Bernhard Englinger, Anna Laemmerer, Patrick Moser, Sebastian Kallus, Clemens Röhrl, Christine Pirker, Dina Baier, Thomas Mohr, Laura Niederstaetter, Samuel M. Meier-Menches, Christopher Gerner, Lisa Gabler, Johannes Gojo, Gerald Timelthaler, Julia Senkiv, Walter Jäger, Christian R. Kowol, Petra Heffeter, Walter Berger

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

Ponatinib is a small molecule multi-tyrosine kinase inhibitor clinically approved for anticancer therapy. Molecular mechanisms by which cancer cells develop resistance against ponatinib are currently poorly understood. Likewise, intracellular drug dynamics, as well as potential microenvironmental factors affecting the activity of this compound are unknown. Cell/molecular biological and analytical chemistry methods were applied to investigate uptake kinetics/subcellular distribution, the role of lipid droplets (LDs) and lipoid microenvironment compartments in responsiveness of FGFR1-driven lung cancer cells toward ponatinib. Selection of lung cancer cells for acquired ponatinib resistance resulted in elevated intracellular lipid levels. Uncovering intrinsic ponatinib fluorescence enabled dissection of drug uptake/retention kinetics in vitro as well as in mouse tissue cryosections, and revealed selective drug accumulation in LDs of cancer cells. Pharmacological LD upmodulation or downmodulation indicated that the extent of LD formation and consequent ponatinib incorporation negatively correlated with anticancer drug efficacy. Co-culturing with adipocytes decreased ponatinib levels and fostered survival of cancer cells. Ponatinib-selected cancer cells exhibited increased LD levels and enhanced ponatinib deposition into this organelle. Our findings demonstrate intracellular deposition of the clinically approved anticancer compound ponatinib into LDs. Furthermore, increased LD biogenesis was identified as adaptive cancer cell-defense mechanism via direct drug scavenging. Together, this suggests that LDs represent an underestimated organelle influencing intracellular pharmacokinetics and activity of anticancer tyrosine kinase inhibitors. Targeting LD integrity might constitute a strategy to enhance the activity not only of ponatinib, but also other clinically approved, lipophilic anticancer therapeutics.

Original languageEnglish
Pages (from-to)1680-1693
Number of pages14
JournalInternational Journal of Cancer
Volume147
Issue number6
DOIs
Publication statusPublished - 15 Sep 2020

Keywords

  • cancer
  • drug sequestration
  • lipid droplets
  • Ponatinib
  • resistance
  • Cell Proliferation
  • Signal Transduction
  • Receptor, Fibroblast Growth Factor, Type 1/antagonists & inhibitors
  • Humans
  • Tumor Microenvironment
  • Drug Resistance, Neoplasm
  • Pyridazines/pharmacokinetics
  • Protein Kinase Inhibitors/pharmacokinetics
  • Xenograft Model Antitumor Assays
  • Animals
  • Imidazoles/pharmacokinetics
  • Lung Neoplasms/drug therapy
  • Cell Line, Tumor
  • Mice
  • Lipid Droplets/metabolism

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