ABCB1 1199G>A polymorphism (rs2229109) affects the transport of imatinib, nilotinib and dasatinib.
ABCB1 (or P-glycoprotein) is implicated in the multidrug-resistance phenotype, including the resistance toward anticancer drugs such as tyrosine kinase inhibitors (TKIs). The purpose of this study was to evaluate in vitro the influence of the ABCB1 1199G>A SNP on ABCB1 transport activity toward selected TKIs (imatinib, nilotinib and dasatinib) that are currently used in chronic myelogenous leukemia.



Two different cell lines, HEK293 and K562, were stably transfected with ABCB1 1199G wild-type or ABCB1 1199A variant allele. The impact of this polymorphism on accumulation and antiproliferative effects of imatinib, nilotinib and dasatinib was evaluated.



In K562 models, the expression of Asn400 variant protein was associated with lower antiproliferative effects of imatinib, nilotinib and dasatinib compared with Ser400 wild-type protein. Moreover, in HEK293 cells, imatinib and nilotinib intracellular accumulation were lower in variant compared with wild-type models.



Imatinib, nilotinib and dasatinib are transported more efficiently by the ABCB1 variant (Asn400) compared with the wild-type (Ser400) protein. The impact of ABCB1 1199G>A SNP on TKI response should be further investigated in chronic myelogenous leukemia patients.
Louvain Centre for Toxicology & Applied Pharmacology, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium.
Géraldine
G
Dessilly
Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium.
Laure
L
Elens
Louvain Centre for Toxicology & Applied Pharmacology, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium.
Nadtha
N
Panin
Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium.
Linda
L
Karmani
De Duve Institute, Université catholique de Louvain, Brussels, Belgium.
Jean-Baptiste
JB
Demoulin
Louvain Centre for Toxicology & Applied Pharmacology, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium.|Department of Clinical Chemistry, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium.
Vincent
V
Haufroid
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D001692:Biological Transport; D000069439:Dasatinib / Q000493:pharmacokinetics*; D057809:HEK293 Cells; D006801:Humans; D000068877:Imatinib Mesylate / Q000493:pharmacokinetics*; D020014:K562 Cells; D020641:Polymorphism, Single Nucleotide; D011743:Pyrimidines / Q000493:pharmacokinetics*
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; D011743:Pyrimidines; D000068877:Imatinib Mesylate; C498826:nilotinib; D000069439:Dasatinib
ABCB1; ABCB1 1199G>A; HEK293; K562; SNP; dasatinib; imatinib; nilotinib