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Int. J. Mol. Sci. 2015, 16(9), 22811-22829; doi:10.3390/ijms160922811

Pharmacogenetics of BCR/ABL Inhibitors in Chronic Myeloid Leukemia

1
Department of Clinical and Experimental Medicine, Section of Pharmacology, University of Pisa, Via Roma 55, 56126 Pisa, Italy
2
Department of Clinical and Experimental Medicine, Section of Hematology, University of Pisa, Via Roma 57, 56126 Pisa, Italy
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Academic Editor: Sabrina Angelini
Received: 30 May 2015 / Revised: 11 September 2015 / Accepted: 14 September 2015 / Published: 21 September 2015
(This article belongs to the Special Issue Pharmacogenetics and Personalized Medicine)
View Full-Text   |   Download PDF [693 KB, uploaded 21 September 2015]   |  

Abstract

Chronic myeloid leukemia was the first haematological neoplasia that benefited from a targeted therapy with imatinib nearly 15 years ago. Since then, several studies have investigated the role of genes, their variants (i.e., polymorphisms) and their encoded proteins in the pharmacokinetics and pharmacodynamics of BCR-ABL1 tyrosine kinase activity inhibitors (TKIs). Transmembrane transporters seem to influence in a significant manner the disposition of TKIs, especially that of imatinib at both cellular and systemic levels. In particular, members of the ATP-binding cassette (ABC) family (namely ABCB1 and ABCG2) together with solute carrier (SLC) transporters (i.e., SLC22A1) are responsible for the differences in drug pharmacokinetics. In the case of the newer TKIs, such as nilotinib and dasatinib, the substrate affinity of these drugs for transporters is variable but lower than that measured for imatinib. In this scenario, the investigation of genetic variants as possible predictive markers has led to some discordant results. With the partial exception of imatinib, these discrepancies seem to limit the application of discovered biomarkers in the clinical settings. In order to overcome these issues, larger prospective confirmative trials are needed. View Full-Text
Keywords: pharmacogenetics; pharmacogenomics; chronic myeloid leukemia; imatinib; nilotinib; dasatinib; bosutinib; ponatinib; transmembrane transporter pharmacogenetics; pharmacogenomics; chronic myeloid leukemia; imatinib; nilotinib; dasatinib; bosutinib; ponatinib; transmembrane transporter
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Polillo, M.; Galimberti, S.; Baratè, C.; Petrini, M.; Danesi, R.; Di Paolo, A. Pharmacogenetics of BCR/ABL Inhibitors in Chronic Myeloid Leukemia. Int. J. Mol. Sci. 2015, 16, 22811-22829.

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