Osimertinib (AZD9291) Enhanced the Efficacy of Chemotherapeutic Agents in ABCB1-and ABCG2-Overexpressing Cells In Vitro, In Vivo, and Ex Vivo
Osimertinib (AZD9291) Enhanced the Efficacy of Chemotherapeutic Agents in ABCB1-and ABCG2-Overexpressing Cells In Vitro, In Vivo, and Ex Vivo
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奥希替尼 (AZD9291) 在体外、体内和离体中增强 ABCB1 和 ABCG2 过表达细胞中化疗药物的疗效
DOI：
10.1158/1535-7163.mct-15-0939
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发表时间：
2016-08-01
影响因子：
5.7
通讯作者：
Fu, Liwu
中科院分区：
文献类型：
--
作者：
Chen, Zhen;Chen, Yifan;Fu, Liwu
atp结合盒（ABC）转运体的过表达已被证明是某些类型癌症中多药耐药（MDR）的主要触发因素。在我们的研究中，我们研究了奥西替尼（AZD9291）是否可以在体外、体内和体外逆转ABCB1和ABCG2诱导的MDR，奥西替尼是一种第三代不可逆酪氨酸激酶抑制剂，既可以激活EGFR突变，也可以激活耐药相关的T790M点突变。我们的研究结果表明，在体外和裸鼠ABCB1-过表达的KBv200细胞移植模型中，奥西替尼显著提高了ABCB1-和abcg2 -过表达细胞对底物化疗药物的敏感性。机制上，奥西替尼通过抑制ABCB1-或abcc2过表达细胞中转运体的外排功能而非亲本敏感细胞中转运体的外排功能，增加了阿霉素（DOX）和罗丹明123 （Rho 123）在细胞内的积累。此外，奥西替尼刺激了ABCB1和ABCG2的atp酶活性，并与与ABCB1或ABCG2结合的[I-125]碘酰亚氮唑啉光标记物竞争，但没有改变ABCB1或ABCG2在mRNA和蛋白质水平上的定位和表达，也没有改变EGFR、AKT和ERK的磷酸化。重要的是，在abcb1过表达的原发性白血病细胞中，奥西替尼还增强了DOX的细胞毒性和Rho 123的细胞内积累。总的来说，这些发现表明，奥西替尼通过抑制ABCB1和ABCG2排出化疗药物来逆转ABCB1和ABCG2介导的多药耐药，并为临床中与奥西替尼联合治疗癌症提供了可能。AACR (C) 2016人。
The overexpression of ATP-binding cassette (ABC) transporters has been proved to be a major trigger for multidrug resistance (MDR) in certain types of cancer. In our study, we investigated whether osimertinib (AZD9291), a third-generation irreversible tyrosine kinase inhibitor of both activating EGFR mutations and resistance-associated T790M point mutation, could reverse MDR induced by ABCB1 and ABCG2 in vitro, in vivo, and ex vivo. Our results showed that osimertinib significantly increased the sensitivity of ABCB1- and ABCG2-overexpressing cells to their substrate chemotherapeutic agents in vitro and in the model of ABCB1-overexpressing KBv200 cell xenograft in nude mice. Mechanistically, osimertinib increased the intracellular accumulations of doxorubicin (DOX) and Rhodamine 123 (Rho 123) by inhibiting the efflux function of the transporters in ABCB1- or ABCG2-overexpressing cells but not in their parental sensitive cells. Furthermore, osimertinib stimulated the ATPase activity of both ABCB1 and ABCG2 and competed with the [I-125] iodoarylazidoprazosin photolabeling bound to ABCB1 or ABCG2, but did not alter the localization and expression of ABCB1 or ABCG2 in mRNA and protein levels nor the phosphorylations of EGFR, AKT, and ERK. Importantly, osimertinib also enhanced the cytotoxicity of DOX and intracellular accumulation of Rho 123 in ABCB1-overexpressing primary leukemia cells. Overall, these findings suggest osimertinib reverses ABCB1- and ABCG2-mediated MDR via inhibiting ABCB1 and ABCG2 from pumping out chemotherapeutic agents and provide possibility for cancer combinational therapy with osimertinib in the clinic. (C)2016 AACR.