Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of São Paulo, Av. Prof. Lineu Prestes, 580, São Paulo, CEP: 05508-000, SP, Brazil.
Med Oncol. 2014 Mar;31(3):851. doi: 10.1007/s12032-014-0851-5. Epub 2014 Jan 29.
Imatinib mesylate (IM) has become a standard of care in chronic myeloid leukemia (CML) therapy. Single nucleotide polymorphisms (SNPs) and altered expression in drug transporter genes may influence IM response. In order to investigate whether mRNA expression and SNPs in drug transporters are associated with IM resistance, we studied 118 chronic-phase CML patients receiving the standard dose of IM (400 mg/day). They were assigned as responders and non-responders according to European LeukemiaNet criteria (2009). mRNA expression in samples at diagnosis (without IM therapy) and outcomes after IM failure were also evaluated in subgroups of patients. Major molecular response (MMR), complete molecular response and primary and secondary resistance were all assessed. BCR-ABL1, ABCB1, ABCG2, SLC22A1 and SLCO1A2 mRNA expression and SNPs in ABCG2 and SLC22A1 genes were analyzed. ABCG2 mRNA expression in the non-responders was higher before and during IM therapy. Furthermore, ABCG2 was overexpressed in those who did not achieve MMR (P=0.027). In a subgroup of patients who switched to second-generation tyrosine kinase inhibitors, high mRNA expression of ABCG2 was associated with a risk of 24 times that of not achieving complete cytogenetic response (OR 24.00, 95% CI 1.74-330.80; P=0.018). In the responder group, patients who achieved MMR (P=0.009) presented higher mRNA levels of SLC22A1. The SNPs were not associated with mRNA expression of ABCG2 and SLC22A1. Our data suggest that elevated ABCG2 expression (an efflux transporter) could be associated with IM resistance and could impact on second-generation TKI response, whereas high SLC22A1 expression (an influx transporter) may be associated with a successful IM therapy in CML patients.
甲磺酸伊马替尼（IM）已成为慢性髓性白血病（CML）治疗的标准治疗方法。药物转运体基因的单核苷酸多态性（SNP）和表达改变可能会影响 IM 反应。为了研究药物转运体的 mRNA 表达和 SNP 是否与 IM 耐药相关，我们研究了 118 例接受 IM 标准剂量（400mg/天）的慢性期 CML 患者。根据欧洲白血病网络标准（2009 年），他们被分为应答者和非应答者。还在患者亚组中评估了诊断时（无 IM 治疗）和 IM 治疗失败后的样本中的 mRNA 表达以及结局。主要分子反应（MMR）、完全分子反应以及原发性和继发性耐药均得到评估。分析了 BCR-ABL1、ABCB1、ABCG2、SLC22A1 和 SLCO1A2 mRNA 表达以及 ABCG2 和 SLC22A1 基因中的 SNP。在 IM 治疗前和治疗期间，非应答者的 ABCG2 mRNA 表达较高。此外，在未达到 MMR 的患者中，ABCG2 过度表达（P=0.027）。在一组转换为第二代酪氨酸激酶抑制剂的患者中，ABCG2 的高 mRNA 表达与未达到完全细胞遗传学反应的风险增加 24 倍相关（OR 24.00，95%CI 1.74-330.80；P=0.018）。在应答者组中，达到 MMR 的患者（P=0.009）具有更高的 SLC22A1 mRNA 水平。SNP 与 ABCG2 和 SLC22A1 的 mRNA 表达无关。我们的数据表明，升高的 ABCG2 表达（外排转运体）可能与 IM 耐药相关，并可能影响第二代 TKI 反应，而高 SLC22A1 表达（内流转运体）可能与 CML 患者的 IM 治疗成功相关。
