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

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

International journal of cancer, 2020-09-15, Vol.147 (6), p.1680-1693 [Peer Reviewed Journal]

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  • Title:
    Lipid droplet‐mediated scavenging as novel intrinsic and adaptive resistance factor against the multikinase inhibitor ponatinib
  • Author: Englinger, Bernhard ; Laemmerer, Anna ; Moser, Patrick ; Kallus, Sebastian ; Röhrl, Clemens ; Pirker, Christine ; Baier, Dina ; Mohr, Thomas ; Niederstaetter, Laura ; Meier‐Menches, Samuel M ; Gerner, Christopher ; Gabler, Lisa ; Gojo, Johannes ; Timelthaler, Gerald ; Senkiv, Julia ; Jäger, Walter ; Kowol, Christian R ; Heffeter, Petra ; Berger, Walter
  • Subjects: drug sequestration ; cancer ; Ponatinib ; lipid droplets ; resistance
  • Is Part Of: International journal of cancer, 2020-09-15, Vol.147 (6), p.1680-1693
  • Description: 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. What's new? Ponatinib is a small‐molecule multi‐tyrosine kinase inhibitor clinically approved for anticancer therapy. However, to date, the intracellular pharmacokinetics of this compound and the molecular mechanisms underlying resistance in cancer cells remain largely unknown. Here, the authors found that ponatinib was selectively scavenged by lipid droplets in cancer cells. Ponatinib accumulation into lipid droplets emerged as a critical determinant of intrinsic and acquired drug resistance. The findings suggest that lipid droplets represent an underestimated organelle influencing intracellular pharmacokinetics and anticancer tyrosine kinase inhibitor activity. Moreover, co‐targeting of lipogenic cancer cell phenotypes might enhance the efficacy of ponatinib and other lipophilic pharmaceuticals.
  • Publisher: Hoboken, USA: John Wiley & Sons, Inc
  • Language: English
  • Identifier: ISSN: 0020-7136
    EISSN: 1097-0215
    DOI: 10.1002/ijc.32924
    PMID: 32064608
  • Source: Wiley Free Content
    Wiley Blackwell Open Access Titles

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