Abstract
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. 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, alpha1-acid glycoprotein. The DNAs from peripheral blood samples in 229 patients were genotyped. 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. 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.
Highlights
Imatinib mesylate (IM) is a selective tyrosine kinase inhibitor, especially against BCR/ABL fusion tyrosine kinase, that has achieved successful treatment outcomes and improved the life quality of chronic myeloid leukemia (CML) patients [1]
Out of 16 single nucleotide polymorphisms (SNP) in 5 genes (ABCB1, multidrug resistance 1; ABCG2, breast-cancer resistance protein; CYP3A5, cytochrome P450-3A5; SLC22A1, human organic cation transporter 1; AGP, a1-acid glycoprotein), SNPs in the ABCG2 and CYP3A5 genes correlated with cytogenetic response to imatinib therapy and SLC22A1 SNP correlated with loss of response or treatment failure to imatinib therapy
We have shown that (a) the treatment outcomes of imatinib therapy can be predicted using the SNP approach in CML patients; (b) the response to imatinib was strongly associated with SNPs for ABCG2 and CYP3A5, and disease stage; and (c) the treatment failure including loss of response (LOR) was associated with SNP for SLC22A1 and disease stage
Summary
Imatinib mesylate (IM) is a selective tyrosine kinase inhibitor, especially against BCR/ABL fusion tyrosine kinase, that has achieved successful treatment outcomes and improved the life quality of chronic myeloid leukemia (CML) patients [1]. In multivariate analyses using Cox proportional hazard models, the disease stage (CP versus AP or BC), the presence of additional cytogenetical abnormality, race (caucasian versus non-caucasian), age, and significant genotypes were considered as covariates for each event: ABCG2 (rs2231137) and CYP3A5 (rs776746) for MCyR and for CCyR; ABCG2 (rs2131142) for MMoR and for CMoR; SLC22A1 (rs683369) for LOR and treatment failure; ABCB1 (rs1045642) for OS; and ABCG2 (rs2131142) and SLC22A1 (rs683369) for dose escalation of IM.
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