Facilitated Transport of EGFR Inhibitors Plays an Important Role in Their Cellular Uptake
- PMID: 38214696
- PMCID: PMC11012238
- DOI: 10.1021/acs.analchem.3c04242
Facilitated Transport of EGFR Inhibitors Plays an Important Role in Their Cellular Uptake
Abstract
Epidermal growth factor receptor (EGFR) is a transmembrane protein commonly targeted by tyrosine kinase inhibitors (TKIs) as a front-line therapy for patients with many cancers including nonsmall cell lung cancer (NSCLC). Effective treatment requires efficient intracellular drug uptake and target binding. However, despite the recent success in the development of new TKI drugs, the mechanisms of uptake for many TKIs are still poorly understood due to the difficulty in imaging and measuring nonfluorescent drug molecules at a subcellular resolution. It has previously been shown that weakly basic TKI drugs are sequestered in lysosomes. Leveraging this property, we apply hyperspectral stimulated Raman scattering imaging to directly visualize and quantify two Food and Drug Administration-approved EGFR inhibitor drugs (lapatinib and afatinib) inside living cells and the changes in their cellular uptake upon the addition of organic cation transporter inhibitors. These single-cell quantitative measurements provide new insight into the role of membrane transporters in the uptake of TKI drugs in living cells.
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References
-
- Giacomini KM; Huang S-M; Tweedie DJ; Benet LZ; Brouwer KLR; Chu X; Dahlin A; Evers R; Fischer V; Hillgren KM; Hoffmaster KA; Ishikawa T; Keppler D; Kim RB; Lee CA; Niemi M; Polli JW; Sugiyama Y; Swaan PW; Ware JA; Wright SH; Wah Yee S; Zamek-Gliszczynski MJ; Zhang L; The International Transporter Consortium. Membrane Transporters in Drug Development. Nat. Rev. Drug Discov. 2010, 9 (3), 215–236. 10.1038/nrd3028. - DOI - PMC - PubMed
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