Synergistic Targeting HER2 and EGFR with Bivalent Aptamer-siRNA Chimera Efficiently Inhibits HER2-Positive Tumor Growth.
Synergistic Targeting HER2 and EGFR with Bivalent Aptamer-siRNA Chimera Efficiently Inhibits HER2-Positive Tumor Growth.
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DOI：
10.1021/acs.molpharmaceut.8b00388
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发表时间：
2018-11-05
影响因子：
4.9
通讯作者：
Liu HY
中科院分区：
文献类型：
--
作者：
Xue L;Maihle NJ;Yu X;Tang SC;Liu HY
HER2在20-30%的乳腺癌和其他癌症中有不同程度的过度表达。尽管针对HER2的单抗与化学药物联合应用改善了表达HER2的患者的疗效，但耐药性和毒性限制了它们的疗效。为了克服耐药性，联合靶向多个HER受体被证明是有效的。EGFR/HER2二聚化可激活PI3K/AKT通路，对HER2靶向药物的耐药性与EGFR上调有关。在这里，我们开发了一种新型的HER2/EGFR靶向核酸疗法，以解决目前的药物限制。新的治疗方法是将HER2适配子-EGFR siRNA正义链和HER2适配子-EGFR siRNA反义链融合成一个分子：二价HER2适配子-EGFR siRNA适体嵌合体(HEH)。在乳腺癌细胞系中，HEH可以被选择性地掺入表达HER2的细胞中，并成功地沉默EGFR基因并下调HER2的表达。在乳腺癌异种移植模型中，HEH能够触发细胞凋亡，降低HER2和EGFR的表达，抑制肿瘤生长。HEH的疗效优于单纯HER2适配子，提示HEH通过靶向HER2和EGFR发挥协同作用。这项研究表明，HEH作为一种新的HER2靶向药物具有巨大的潜力，可以解决现有药物的毒性和耐药性，并可能为许多HER2阳性的癌症提供治疗方法。
HER2 overexpression is identified on 20–30% breast cancer and other cancers at different levels. Although HER2 targeted monoclonal antibody combined with chemical drugs has shown improved outcomes in HER2 expressing patients, drug resistance and toxicity have limited their efficacy. To overcome drug resistance, cotargeting multiple HER receptors was proven to be effective. EGFR/HER2 dimerization can active PI3K/AKT pathway, and resistance to HER2-targeted drugs is associated with upregulation of EGFR. Here, we developed a novel HER2/EGFR targeted nucleic acid therapeutic to address current drug limits. The new therapeutic is constructed by fusing HER2 aptamer-EGFR siRNA sense strand with HER2 aptamer-EGFR siRNA antisense strand into one molecule: a bivalent HER2 aptamer-EGFR siRNA aptamer chimera (HEH). In breast cancer cell lines, HEH can be selectively taken up into HER2 expressing cells and successfully silence EGFR gene and down regulate HER2 expression. In breast cancer xenograft models, HEH is capable of triggering cell apoptosis, decreasing HER2 and EGFR expression, and suppressing tumor growth. The therapeutic efficacy of HEH is superior to HER2 aptamer only, which suggests that HEH has synergistic effect by targeting HER2 and EGFR. This study demonstrated that HEH has great potential as a new HER2 targeted drug to address toxicity and resistance of current drugs and may provide a cure for many HER2 positive cancers.
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影响因子：
46.9
作者：
Dassie, Justin P.;Liu, Xiu-ying;Thomas, Gregory S.;Whitaker, Ryan M.;Thiel, Kristina W.;Stockdale, Katie R.;Meyerholz, David K.;McCaffrey, Anton P.;McNamara, James O., II;Giangrande, Paloma H.
通讯作者：
Giangrande, Paloma H.
影响因子：
4.6
作者：
Liu HY;Yu X;Liu H;Wu D;She JX
通讯作者：
She JX
影响因子：
--
作者：
Boomer, RM;Lewis, SD;McCauley, TG
通讯作者：
McCauley, TG
DOI：
10.1089/mab.2017.0052
发表时间：
2018-02-01
影响因子：
--
作者：
Kaneko, Mika K.;Yamada, Shinji;Kato, Yukinari
通讯作者：
Kato, Yukinari
DOI：
10.1158/1078-0432.ccr-14-1432
发表时间：
2015-02-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Pollock NI;Grandis JR
通讯作者：
Grandis JR