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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\u2010driven 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 <jats:italic>in vitro<\/jats:italic> 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\u2010culturing with adipocytes decreased ponatinib levels and fostered survival of cancer cells. Ponatinib\u2010selected 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\u2010defense mechanism <jats:italic>via<\/jats:italic> 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.<\/jats:p>","DOI":"10.1002\/ijc.32924","type":"journal-article","created":{"date-parts":[[2020,2,17]],"date-time":"2020-02-17T05:18:15Z","timestamp":1581916695000},"page":"1680-1693","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Lipid droplet\u2010mediated scavenging as novel intrinsic and adaptive resistance factor against the multikinase inhibitor ponatinib"],"prefix":"10.1002","volume":"147","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9701-2600","authenticated-orcid":false,"given":"Bernhard","family":"Englinger","sequence":"first","affiliation":[{"name":"Department of Medicine I, Medical University of Vienna Institute of Cancer Research and Comprehensive Cancer Center  Vienna Austria"},{"name":"Research Cluster \u201cTranslational 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