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Rociletinib (CO-1686) enhanced the efficacy of chemotherapeutic agents in ABCG2-overexpressing cancer cells in vitro and in vivo.
Acta Pharmaceutica Sinica B ( IF 14.5 ) Pub Date : 2020-01-26 , DOI: 10.1016/j.apsb.2020.01.008
Fanpu Zeng 1, 2 , Fang Wang 2 , Zongheng Zheng 1 , Zhen Chen 2 , Kenneth Kin Wah To 3 , Hong Zhang 2 , Qian Han 4 , Liwu Fu 2
Affiliation  

Overexpression of adenosine triphosphate (ATP)-binding cassette subfamily G member 2 (ABCG2) in cancer cells is known to cause multidrug resistance (MDR), which severely limits the clinical efficacy of chemotherapy. Currently, there is no FDA-approved MDR modulator for clinical use. In this study, rociletinib (CO-1686), a mutant-selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), was found to significantly improve the efficacy of ABCG2 substrate chemotherapeutic agents in the transporter-overexpressing cancer cells in vitro and in MDR tumor xenografts in nude mice, without incurring additional toxicity. Mechanistic studies revealed that in ABCG2-overexpressing cancer cells, rociletinib inhibited ABCG2-mediated drug efflux and increased intracellular accumulation of ABCG2 probe substrates. Moreover, rociletinib, inhibited the ATPase activity, and competed with [125I] iodoarylazidoprazosin (IAAP) photolabeling of ABCG2. However, ABCG2 expression at mRNA and protein levels was not altered in the ABCG2-overexpressing cells after treatment with rociletinib. In addition, rociletinib did not inhibit EGFR downstream signaling and phosphorylation of protein kinase B (AKT) and extracellular signal-regulated kinase (ERK). Our results collectively showed that rociletinib reversed ABCG2-mediated MDR by inhibiting ABCG2 efflux function, thus increasing the cellular accumulation of the transporter substrate anticancer drugs. The findings advocated the combination use of rociletinib and other chemotherapeutic drugs in cancer patients with ABCG2-overexpressing MDR tumors.



中文翻译:

在体外和体内,Rociletinib(CO-1686)增强了过表达ABCG2癌细胞中化学治疗剂的功效。

已知在癌细胞中过磷酸三磷酸腺苷(ATP)结合盒亚家族G成员2(ABCG2)的过度表达会引起多药耐药性(MDR),严重限制了化学疗法的临床疗效。当前,尚无FDA批准的临床MDR调节剂。在这项研究中,发现罗考替尼(CO-1686)是一种突变选择性表皮生长因子受体(EGFR)酪氨酸激酶抑制剂(TKI),可显着提高ABCG2底物化学治疗剂在体外过表达转运蛋白的癌细胞中的功效。以及裸鼠的MDR肿瘤异种移植,而不会产生额外的毒性。机理研究表明,在过表达ABCG2的癌细胞中,rociletinib抑制ABCG2介导的药物外流并增加ABCG2探针底物的细胞内积累。此外,罗考替尼抑制ATPase活性,并与[ 125I] ABCG2的碘代芳基叠氮唑嗪(IAAP)光标记。但是,用罗来替尼治疗后,在过表达ABCG2的细胞中,在mRNA和蛋白质水平上的ABCG2表达没有改变。此外,罗考替尼不抑制EGFR下游信号传导和蛋白激酶B(AKT)和细胞外信号调节激酶(ERK)的磷酸化。我们的结果共同表明,罗考替尼通过抑制ABCG2外排功能逆转了ABCG2介导的MDR,从而增加了转运底物抗癌药物的细胞蓄积。该发现提倡将罗卡替尼和其他化学治疗药物联合用于过度表达ABCG2的MDR肿瘤患者。

更新日期:2020-01-26
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