Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan.
Department of Education and Research Center for Community Medicine, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Aichi, 467-8601, Japan.
BMC Cancer. 2019 Mar 19;19(1):246. doi: 10.1186/s12885-019-5438-2.
Docetaxel is a widely used cytotoxic agent for treatments of various cancers. The ATP binding cassette (ABC) transporter / multidrug resistance protein (MRP) ABCC10/MRP7, involved in transporting taxanes, has been associated with resistance to these agents. Since genetic variation in drug transporters may affect clinical outcomes, we examined whether polymorphism of ABCC10 could affect clinical responses to docetaxel.
Using 18 NSCLC cell lines and CRISPR-based genome-edited HeLa cells, we analyzed whether genetic variants of ABCC10 (rs2125739, rs9349256) affected cytotoxicity to docetaxel. Subsequently, we analyzed genetic variants [ABCC10 (rs2125739), ABCB1 (C1236T, C3435T, G2677 T/A), ABCC2 (rs12762549), and SLCO1B3 (rs11045585)] in 69 blood samples of NSCLC patients treated with docetaxel monotherapy. Clinical outcomes were evaluated between genotype groups.
In the cell lines, only one genetic variant (rs2125739) was significantly associated with docetaxel cytotoxicity, and this was confirmed in the genome-edited cell line. In the 69 NSCLC patients, there were no significant differences related to rs2125739 genotype in terms of RR, PFS, or OS. However, this SNP was associated with grade 3/4 neutropenia (T/C group 60% vs. T/T group 87%; P = 0.028). Furthermore, no patient with a T/C genotype experienced febrile neutropenia.
Our results indicate that genetic variation in the ABCC10 gene is associated with neutropenia for docetaxel treatment.
多西紫杉醇是一种广泛用于治疗各种癌症的细胞毒性药物。参与运输紫杉烷的 ABC 转运蛋白/多药耐药蛋白（MRP）ABCC10/MRP7 与这些药物的耐药性有关。由于药物转运蛋白的遗传变异可能影响临床结局，我们研究了 ABCC10 多态性是否会影响多西紫杉醇的临床反应。
使用 18 种 NSCLC 细胞系和基于 CRISPR 的基因编辑 HeLa 细胞，我们分析了 ABCC10 的遗传变异（rs2125739、rs9349256）是否影响多西紫杉醇的细胞毒性。随后，我们分析了 69 名接受多西紫杉醇单药治疗的 NSCLC 患者的血液样本中的遗传变异（ABCC10 [rs2125739]、ABCB1 [C1236T、C3435T、G2677T/A]、ABCC2 [rs12762549]和 SLCO1B3 [rs11045585]）。在基因型组之间评估了临床结局。
在细胞系中，只有一个遗传变异（rs2125739）与多西紫杉醇的细胞毒性显著相关，这在基因编辑的细胞系中得到了证实。在 69 名 NSCLC 患者中，rs2125739 基因型与 RR、PFS 或 OS 均无显著相关性。然而，该 SNP 与 3/4 级中性粒细胞减少症相关（T/C 组 60% vs. T/T 组 87%；P=0.028）。此外，没有 T/C 基因型的患者发生发热性中性粒细胞减少症。
我们的结果表明，ABCC10 基因的遗传变异与多西紫杉醇治疗的中性粒细胞减少有关。
