Alectinib is used as a first-line treatment for anaplastic lymphoma kinase (ALK)-rearranged non–small cell lung cancer (NSCLC). Whereas other ALK inhibitors have been reported to be involved in resistance to ATP-binding cassette (ABC) transporters, no data are available regarding the association between resistance to alectinib and ABC-transporters. To investigate whether ABC-transporters contribute to alectinib resistance, ABC-transporter expression in alectinib-resistant cell lines derived from a patient with ALK-rearranged NSCLC and from H2228 lung cancer cells was evaluated and compared with that in each parent cell type. ATP-binding cassette subfamily C member 11 (ABCC11) expression was significantly increased in alectinib-resistant cell lines compared with that in alectinib-sensitive lines. ABCC11 inhibition increased sensitivity to alectinib in vitro. ABCC11-overexpressing cells were established by transfection of an ABCC11 expression vector into H2228 cells, while control cells were established by transfecting H2228 cells with an empty vector. ABCC11-overexpressing cells exhibited decreased sensitivity to alectinib compared with that of control cells in vitro. Moreover, the tumor growth rate following alectinib treatment was higher in ABCC11-overexpressing cells than that in control cells in vivo. In addition, the intracellular alectinib concentration following exposure to 100 nmol/L alectinib was significantly lower in the ABCC11-overexpressing cell line compared with that in control cells. This is the first preclinical evidence showing that ABCC11 expression may be involved in acquired resistance to alectinib.

中文翻译：

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临床配对耐药模型中 ABCC11/MRP8 过度表达导致 ALK 重排肺癌患者对艾乐替尼的获得性耐药

艾乐替尼被用作间变性淋巴瘤激酶 (ALK) 重排非小细胞肺癌 (NSCLC) 的一线治疗。尽管据报道其他 ALK 抑制剂与对 ATP 结合盒 (ABC) 转运蛋白的抗性有关，但没有关于对艾乐替尼和 ABC 转运蛋白的抗性之间关联的数据。为了研究 ABC 转运蛋白是否导致艾乐替尼耐药，评估了来自 ALK 重排 NSCLC 患者和 H2228 肺癌细胞的艾乐替尼耐药细胞系中的 ABC 转运蛋白表达，并与每种亲本细胞类型进行了比较。与艾乐替尼敏感细胞系相比，艾乐替尼耐药细胞系中 ATP 结合盒亚家族 C 成员 11 (ABCC11) 的表达显着增加。ABCC11 抑制增加了体外艾乐替尼的敏感性。ABCC11 过表达细胞是通过将 ABCC11 表达载体转染到 H2228 细胞中来建立的，而对照细胞是通过用空载体转染 H2228 细胞来建立的。与体外对照细胞相比，ABCC11 过表达细胞对艾乐替尼的敏感性降低。此外，在体内 ABCC11 过表达细胞中，艾乐替尼治疗后的肿瘤生长率高于对照细胞。此外，与对照细胞相比，ABCC11 过表达细胞系中暴露于 100 nmol/L 艾乐替尼后的细胞内艾乐替尼浓度显着降低。这是第一个临床前证据表明 ABCC11 表达可能与对艾乐替尼的获得性耐药有关。ABCC11 过表达细胞是通过将 ABCC11 表达载体转染到 H2228 细胞中来建立的，而对照细胞是通过用空载体转染 H2228 细胞来建立的。与体外对照细胞相比，ABCC11 过表达细胞对艾乐替尼的敏感性降低。此外，在体内 ABCC11 过表达细胞中，艾乐替尼治疗后的肿瘤生长率高于对照细胞。此外，与对照细胞相比，ABCC11 过表达细胞系中暴露于 100 nmol/L 艾乐替尼后的细胞内艾乐替尼浓度显着降低。这是第一个临床前证据表明 ABCC11 表达可能与对艾乐替尼的获得性耐药有关。ABCC11 过表达细胞是通过将 ABCC11 表达载体转染到 H2228 细胞中来建立的，而对照细胞是通过用空载体转染 H2228 细胞来建立的。与体外对照细胞相比，ABCC11 过表达细胞对艾乐替尼的敏感性降低。此外，在体内 ABCC11 过表达细胞中，艾乐替尼治疗后的肿瘤生长率高于对照细胞。此外，与对照细胞相比，ABCC11 过表达细胞系中暴露于 100 nmol/L 艾乐替尼后的细胞内艾乐替尼浓度显着降低。这是第一个临床前证据表明 ABCC11 表达可能与对艾乐替尼的获得性耐药有关。