Single-nucleotide polymorphisms of ABCG2 increase the efficacy of tyrosine kinase inhibitors in the K562 chronic myeloid leukemia cell line
2014 (English)In: Pharmacogenetics & Genomics, ISSN 1744-6872, E-ISSN 1744-6880, Vol. 24, no 1, 52-61 p.Article in journal (Refereed) Published
ObjectiveThe tyrosine kinase inhibitors (TKIs) used in the treatment of chronic myeloid leukemia are substrates for the efflux transport protein ATP-binding cassette subfamily G member 2 (ABCG2). Variations in ABCG2 activity might influence pharmacokinetics and therapeutic outcome of TKIs. The role of ABCG2 single-nucleotide polymorphisms (SNPs) in TKI treatment is not clear and functional in-vitro studies are lacking. The aim of this study was to investigate the consequences of ABCG2 SNPs for transport and efficacy of TKIs [imatinib, N-desmethyl imatinib (CGP74588), dasatinib, nilotinib, and bosutinib].Materials and methodsABCG2 SNPs 34Ggreater thanA, 421Cgreater thanA, 623Tgreater thanC, 886Ggreater thanC, 1574Tgreater thanG, and 1582Ggreater thanA were constructed from ABCG2 wild-type cDNA and transduced to K562 cells by retroviral gene transfer. Variant ABCG2 expression in cell membranes was evaluated and the effects of ABCG2 SNPs on transport and efficacy of TKIs were measured as the ability of ABCG2 variants to protect against TKI cytotoxicity.ResultsWild-type ABCG2 had a protective effect against the cytotoxicity of all investigated compounds except bosutinib. It was found that ABCG2 expression provided better protection against CGP74588 than its parent compound, imatinib. ABCG2 421Cgreater thanA, 623Tgreater thanC, 886Ggreater thanC, and 1574Tgreater thanG reduced cell membrane expression of ABCG2 and the protective effect of ABCG2 against imatinib, CGP74588, dasatinib, and nilotinib cytotoxicity.ConclusionThese findings show that the ABCG2 SNPs 421Cgreater thanA, 623Tgreater thanC, 886Ggreater thanC, and 1574Tgreater thanG increase the efficacy of investigated TKIs, indicating a reduced transport function that might influence TKI pharmacokinetics in vivo. Furthermore, the active imatinib metabolite CGP74588 is influenced by ABCG2 expression to a greater extent than the parent compound.
Place, publisher, year, edition, pages
Lippincott, Williams andamp; Wilkins , 2014. Vol. 24, no 1, 52-61 p.
ABCG2; CGP74588; chronic myeloid leukemia; imatinib; N-desmethyl imatinib; pharmacogenetics; single-nucleotide polymorphism; tyrosine kinase inhibitor
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:liu:diva-103285DOI: 10.1097/FPC.0000000000000022ISI: 000328629800007OAI: oai:DiVA.org:liu-103285DiVA: diva2:688501