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Clinical Relevance of a Pharmacogenetic Approach Using Cancer Therapy: Clinical Clinical Relevance of a Pharmacogenetic Approach Using Multiple Candidate Genes to Predict Response and Resistance to Imatinib Therapy in Chronic Myeloid Leukemia Dong Hwan (Dennis) Kim,1, 5 Lakshmi Sriharsha,1 Wei Xu,2 Suzanne Kamel-Reid,3 Xiangdong Liu,4 Katherine Siminovitch,4 Hans A. Messner,1and Jeffrey H. Lipton1 Abstract Purpose: Imatinib resistance is major cause of imatinib mesylate (IM) treatment failure in chronic myeloid leukemia (CML) patients. Several cellular and genetic mechanisms of imatinib resistance have been proposed, including amplification and overexpression of the BCR/ABL gene, the tyrosine kinase domain point mutations, and MDR1 gene overexpression. Experimental Design: We investigated the impact of 16 single nucleotide polymorphisms (SNP) in five genes potentially associated with pharmacogenetics of IM, namely ABCB1, multidrug resistance 1; ABCG2, breast-cancer resistance protein; CYP3A5,cytochrome P450-3A5; SLC22A1, human organic cation transporter 1; and AGP, a1-acid glycoprotein. The DNAs from peripheral blood samples in 229 patients were genotyped. Results: The GG genotype in ABCG2 (rs2231137), AA genotype in CYP3A5 (rs776746), and advanced stage were significantly associated with poor response to IM especially for major or complete cytogenetic response, whereas the GG genotype at SLC22A1 (rs683369) and advanced stage correlated with high rate of loss of response or treatment failure to IM therapy. Conclusions: We showed that the treatment outcomes of imatinib therapy could be predicted using a novel, multiple candidate gene approach based on the pharmacogenetics of IM. Imatinib mesylate (IM) is a selective tyrosine kinase inhibitor, amplification andoverexpression of the BCR/ABL gene, point especially against BCR/ABL fusion tyrosine kinase, that has mutations in the ATP-binding site with kinase reactivation (3), achievedsuccessful treatment outcomes andimprovedthe life or overexpression of the MDR1 gene (4). quality of chronic myeloidleukemia (CML) patients (1). The It has been well establishedthat the response to imatinib activity of IM is mediated by blocking the activity of BCR/ABL therapy is strongly associatedwith the diseasefactor such as tyrosine kinase in CML cells. However, some of the patients disease stage, that is, chronic phase (CP), accelerated phase fail to achieve optimal response, anda substantial proportion (AP), or blastic crisis (BC). Besides the disease factor, several of patients develop resistance to IM (2). Several molecular determinants were known to be associated with the pharmaco- mechanisms leading to IM resistance have been proposed: kinetics of imatinib with respect to absorption, distribution, and metabolism, influencing the systemic levels or intracellular concentration of imatinib which affects the response of imatinib therapy (Supplemental Table S1; ref. 5). IM is a substrate for the Authors’ Affiliations: 1Chronic Myelogenous Leukemia Group, Department of adenosine triphosphate binding cassette (ABC) transporters, 2 Hematology/Medical Oncology, Department of Biostatistics, Princess Margaret ABCB1 andABCG2, whereas the active uptake of IM into cells is Hospital, and 3Department of Pathology, University Health Network, University of Toronto, and 4Analytical GeneticsTechnology Centre, University Health Network, mediated by the human organic cationic transporter-1 (OCT1; Toronto, Ontario, Canada; and 5Department of Hematology/Oncology, Samsung SLC22A1). Also, IM is metabolizedthrough first-pass drug Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea metabolism by the cytochrome P450 - CYP3A4 andCYP3A5. In Received1/22/09; revised 3/20/09; accepted3/23/09; publishedOnlineFirst 7/7/09. addition, it is delivered in a bound form with a plasma protein Grant support: Korea Healthcare Technology R&D Project, Ministry of Health referredto as a1-acidglycoprotein (AGP). Welfare & Family Affairs, Republic of Korea (A070001) and by a grant from the Friends to life fund, Princess Margaret Hospital foundation,Toronto, Ontario, Canada. Accordingly, the intracellular or systemic level of imatinib The costs of publication of this article were defrayed in part by the payment of page shouldbe influencedby these factors, such as the ABCB1, charges. This article must therefore be hereby marked advertisement in accordance ABCG2, SLC22A1, CYP3A4, CYP3A5,orAGP genes (6). The with 18 U.S.C. Section 1734 solely to indicate this fact. interindividual variability of five candidate genes associated Note: Supplementary data for this article are available at Clinical Cancer Research ABCB1 Online (http://clincancerres.aacrjournals.org/). with drug transport/metabolism, namely, (4, 7–9), This work was presented at the annual meeting of American Society of Hematology, ABCG2 (10–12), SLC22A1 (13–16), CYP3A4/3A5 (6, 17, 18), Atlanta, GA, USA, 2007. and AGP (19–22), couldaffect the expression of corresponding Requests for reprints: Dong Hwan (Dennis) Kim, Department of Hematology/ proteins, thus influencing the treatment outcomes of imatinib Oncology, Samsung Medical Center, Sungkyunkwan University, Seoul, Korea, therapy. We hypothesizedthat the SNPs of these five genes 135-710. Phone: 82-2-3410-3459; Fax: 82-2-3410-0041; E-mail: drkiim @ medimail.co.kr. couldpredict the outcomes of imatinib therapy in CML F 2009 American Association for Cancer Research. patients. We evaluatedits efficacy by three categories of doi:10.1158/1078-0432.CCR-09-0145 parameters: (a) response to imatinib therapy [hematologic Clin Cancer Res 2009;15(14) July 15, 2009 4750 www.aacrjournals.org Downloaded from clincancerres.aacrjournals.org on September 29, 2021. © 2009 American Association for Cancer Research. Pharmacogenetics of Imatinib Therapy for CML ABL fusion gene transcripts was repeatedevery 3 mo regardlessof Translational Relevance cytogenetic response using quantitative BCR/ABL mRNA PCR. Sequenom MassARRAY genotyping system. In the initial step, the The current study attempted to investigate the predictive candidate genotypes were selected by the literature review. If there was role of multiple candidate gene single nucleotide poly- no available data in the literature review, we referred to the SNPs from morphisms (SNP) associated with the metabolism/trans- the Entrez SNP site (http://www.ncbi.nlm.nih.gov/sites/entrez). The port of imatinib for the treatment of chronic myeloid selection criteria for the SNP were the nonsynonymous SNPs in exon region with minor allele frequency of >0.05 to 0.1. If we couldnot find leukemia. Several biomarkers were suggested to predict any SNPs satisfying the criteria, we included synonymous SNPs in the response or resistance to imatinib therapy, such as the exon region or SNPs with minor allele frequency of <0.05. IC 50 cell assay, OCT1activity assay, or blood trough level Genotyping was undertaken using the Sequenom iPLEX platform, measurement. We hypothesized that pharmacogenetic according to the manufacturer’s instructions (www.sequenom.com; information can be utilized to predict the response to ima- Sequenom Inc.). Whole bloodsamples were obtainedaccordingto the tinib therapy. Out of 16 SNPs in 5 genes (ABCB1,multidrug declaration of Helsinki. DNA was extracted using the Puregene DNA resistance 1; ABCG2, breast-cancer resistance protein; purification Kit (Gentra Systems Inc.). The detection of SNPs was done CYP3A5, cytochrome P450-3A5; SLC22A1, human or- by the analysis of primer extension products generated from previously ganic cation transporter 1; AGP, a1-acid glycoprotein), amplifiedgenomic DNA using a Sequenom chip-basedmatrix-assisted SNPs in the ABCG2 and CYP3A5 genes correlated with laser desorption/ionization time-of-flight (MALDI-TOF) mass spec- cytogenetic response to imatinib therapy and SLC22A1 trometry platform. Multiplex SNP assays were designed using Spec- troDesigner software (Sequenom). Ninety-six-well plates containing 2.5 SNP correlated with loss of response or treatment failure ngDNAineachwellwereamplifiedbyPCRfollowingthe to imatinib therapy. Based on the results from single marker specifications of Sequenom. Unincorporatednucleotidesin the PCR analyses, we established the predictive model for the product were deactivated using shrimp alkaline phosphatase. Allele response or treatment failure to imatinib therapy.The pres- discrimination reactions were conducted by adding the extension ent results can be used to identify high-risk group of primer(s), DNA polymerase, and a cocktail mixture of deoxynucleotide patients with CML who potentially need dose escalation triphosphates and di-deoxynucleotide triphosphates to each well. of imatinib or to switch to second-generation tyrosine MassExtend clean resin (Sequenom) was added to the mixture to kinase inhibitors. remove extraneous salts that couldinterfere with MALDI-TOF analysis. The primer extension products were then cleaned and spotted onto a SpectroChip. Genotypes were determined by spotting an aliquot of each sample onto a 384 SpectroChip (Sequenom), which was sub- response, major/complete cytogenetic response (MCyR/CCyR), sequently readby the MALDI-TOF mass spectrometer. Duplicate major/complete molecular response (MMoR/CMoR)]; (b) treat- samples andnegative controls were includedto check genotyping ment failure [loss of response (LOR), primary resistance, prog- quality. Genotyping results were confirmedusing directsequencing in n ression to AP or BC]; and(c ) dose escalation for the purpose selectedsamples ( = 20). The sequences of primers are listedin
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