ABCB1 1199G>A polymorphism (rs2229109) affects the transport of imatinib, nilotinib and dasatinib

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Géraldine Dessilly1, Laure Elens2, Nadtha Panin1

  • 1Louvain Centre for Toxicology & Applied Pharmacology, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium.

Pharmacogenomics
|June 9, 2016
PubMed
Abstract

Insights

The ABCB1 1199G>A single nucleotide polymorphism (SNP) affects tyrosine kinase inhibitor (TKI) transport. This variant protein shows increased TKI transport, potentially impacting chronic myelogenous leukemia treatment response.

Area of Science:

  • Pharmacogenomics
  • Molecular Biology
  • Oncology

Background:

  • ABCB1 (P-glycoprotein) mediates multidrug resistance, affecting anticancer drug efficacy.
  • Tyrosine kinase inhibitors (TKIs) are crucial in chronic myelogenous leukemia (CML) treatment.
  • Genetic variations in ABCB1 may influence TKI response.

Purpose of the Study:

  • To investigate the in vitro impact of the ABCB1 1199G>A single nucleotide polymorphism (SNP) on ABCB1 transport activity.
  • To evaluate the influence of this SNP on the accumulation and antiproliferative effects of imatinib, nilotinib, and dasatinib.

Main Methods:

  • Stable transfection of HEK293 and K562 cell lines with wild-type (1199G) or variant (1199A) ABCB1 alleles.
  • Assessment of intracellular accumulation of TKIs in transfected cells.
  • Evaluation of antiproliferative effects of TKIs in relation to ABCB1 genotype.

Main Results:

  • The ABCB1 1199A variant (Asn400) exhibited lower antiproliferative effects for imatinib, nilotinib, and dasatinib in K562 cells compared to the wild-type (Ser400).
  • Intracellular accumulation of imatinib and nilotinib was reduced in HEK293 cells expressing the ABCB1 1199A variant compared to the wild-type.
  • The variant ABCB1 protein (Asn400) demonstrated more efficient transport of imatinib, nilotinib, and dasatinib than the wild-type protein (Ser400).

Conclusions:

  • The ABCB1 1199G>A SNP influences the transport activity of ABCB1 for imatinib, nilotinib, and dasatinib.
  • The variant ABCB1 protein facilitates more efficient TKI transport, potentially contributing to reduced drug efficacy.
  • Further clinical investigation of the ABCB1 1199G>A SNP's impact on TKI response in CML patients is warranted.
Keywords:
ABCB1ABCB1 1199G>AHEK293K562SNPdasatinibimatinibnilotinib

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