Facilitated Transport of EGFR Inhibitors Plays an Important Role in Their Cellular Uptake

Area of Science:

• Biochemistry
• Cell Biology
• Pharmacology

Background:

• Epidermal growth factor receptor (EGFR) is a key target in cancer therapy, notably for non-small cell lung cancer (NSCLC).
• Tyrosine kinase inhibitors (TKIs) are crucial EGFR-targeted drugs, but their intracellular uptake mechanisms remain poorly understood.
• Visualizing nonfluorescent drug molecules at subcellular resolution is challenging, hindering the study of TKI uptake.

Purpose of the Study:

• To directly visualize and quantify the intracellular uptake of FDA-approved EGFR inhibitor drugs (lapatinib and afatinib) in living cells.
• To investigate the role of membrane transporters in TKI drug uptake.
• To understand how organic cation transporter inhibitors affect TKI cellular uptake.

Main Methods:

• Hyperspectral stimulated Raman scattering (SRS) imaging was employed to visualize nonfluorescent TKI drugs.
• Single-cell quantitative measurements were performed to assess drug uptake.
• The effect of organic cation transporter inhibitors on TKI uptake was evaluated.

Main Results:

• Hyperspectral SRS imaging successfully visualized and quantified two EGFR inhibitors (lapatinib and afatinib) within living cells.
• The study demonstrated changes in cellular uptake of TKIs upon the addition of organic cation transporter inhibitors.
• Lysosomal sequestration of weakly basic TKIs was leveraged for imaging.

Conclusions:

• Membrane transporters play a significant role in the cellular uptake of TKI drugs.
• This research provides new insights into TKI drug mechanisms using advanced imaging techniques.
• The findings contribute to understanding drug delivery for effective cancer treatment.