Interactions of ABCG2 (BCRP) with epidermal growth factor receptor kinase inhibitors developed for molecular imaging

Area of Science:

• Pharmacology
• Molecular Imaging
• Biochemistry

Background:

• Novel epidermal growth factor receptor kinase inhibitors (EGFRIs) are developed for positron emission tomography (PET) imaging.
• Breast cancer resistance protein (BCRP/ABCG2) is a major efflux transporter that can affect drug distribution and efficacy.
• Understanding the interaction between EGFRIs and BCRP is crucial for accurate PET imaging interpretation.

Purpose of the Study:

• To investigate the in vitro interactions between novel EGFRIs and BCRP.
• To determine if EGFRIs are substrates or inhibitors of BCRP.
• To assess the impact of BCRP on the distribution of EGFRIs in cells.

Main Methods:

• In vitro ATPase activity assays using BCRP-overexpressing Madin-Darbey canine kidney (MDCK) cells.
• Cell proliferation assays to determine drug resistance.
• Immunoblotting to confirm BCRP expression in relevant cell lines.

Main Results:

• Five of seven tested EGFRIs activated BCRP ATPase to varying degrees.
• BCRP overexpression conferred resistance to four specific EGFRIs (ML04, ML06, methoxy-Br-ML03, PEG6-ML05).
• No significant inhibition of BCRP by EGFRIs was observed at submicromolar concentrations.

Conclusions:

• EGFRIs can interact with and be transported by BCRP, influencing their in vivo distribution.
• The observed radioactivity signals in tumor xenografts reflect both transporter activity and target binding.
• Co-administration of efflux transporter inhibitors may aid in differentiating BCRP-mediated distribution from EGFR binding in PET imaging.