Human ABC transporter ABCG2/BCRP expression in chemoresistance: basic and clinical perspectives for molecular cancer...

Area of Science:

• Biochemistry
• Molecular Biology
• Pharmacology

Background:

• Adenine triphosphate (ATP)-binding cassette (ABC) transporters, including ABCB1/P-glycoprotein (P-gp) and ABCG2/breast cancer resistance protein (BCRP), facilitate cellular efflux of diverse compounds.
• ABCG2/BCRP, a half-type ABC transporter functioning as a homodimer, actively transports numerous anticancer agents like irinotecan, SN-38, gefitinib, imatinib, methotrexate, and mitoxantrone.
• The expression of ABCG2/BCRP is implicated in multidrug resistance in cancer cells and influences drug absorption, distribution, metabolism, and excretion (ADME) in normal tissues, thereby modulating chemotherapy efficacy in vivo.

Purpose of the Study:

• To elucidate the substrate preferences and structural characteristics of ABCG2/BCRP to better understand its in vivo mechanisms during chemotherapy.
• To investigate the role of ABCG2/BCRP single-nucleotide polymorphisms (SNPs) in determining chemotherapeutic efficacy and potential adverse effects.
• To examine the interaction of novel molecular-targeted cancer drugs, such as tyrosine kinase inhibitors, with ABCG2/BCRP and their impact on pharmacokinetics and pharmacodynamics.

Main Methods:

• Literature review and analysis of existing data on ABCG2/BCRP function and substrate interactions.
• Examination of studies detailing the impact of ABCG2/BCRP expression and SNPs on drug response.
• Analysis of research on the pharmacogenetics of ABCG2/BCRP in the context of molecular-targeted therapies.

Main Results:

• ABCG2/BCRP actively effluxes various anticancer drugs, contributing to multidrug resistance and altered drug disposition.
• ABCG2/BCRP SNPs can significantly affect its functional activity, potentially leading to unexpected adverse drug reactions at standard doses.
• Many modern molecular-targeted drugs, including tyrosine kinase inhibitors like imatinib and gefitinib, are substrates or modulators of ABCG2/BCRP activity.

Conclusions:

• Clarifying ABCG2/BCRP substrate specificity and structure is vital for understanding its role in chemotherapy outcomes.
• The pharmacogenetics of ABCG2/BCRP, including functional SNPs and interactions with targeted therapies, are critical considerations for personalized cancer treatment.
• Targeting ABCG2/BCRP activity or accounting for its genetic variations may enhance the efficacy and safety of both conventional and molecular-targeted chemotherapies.