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.

中文翻译：

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与二价适体-siRNA嵌合体协同靶向HER2和EGFR可有效抑制HER2阳性肿瘤的生长。

在20-30％的乳腺癌和其他不同水平的癌症中发现HER2过表达。尽管HER2靶向单克隆抗体与化学药物联用已在表达HER2的患者中显示出改善的结果，但耐药性和毒性限制了它们的疗效。为了克服耐药性，共靶向多种HER受体被证明是有效的。EGFR / HER2二聚化可以激活PI3K / AKT途径，并且对HER2靶向药物的耐药性与EGFR的上调相关。在这里，我们开发了一种新型的HER2 / EGFR靶向核酸治疗剂，以解决当前的药物限制。通过将HER2适体-EGFR siRNA反义链与HER2适体-EGFR siRNA反义链融合成一个分子：二价HER2适体-EGFR siRNA适体嵌合体（HEH），构建了新的治疗剂。在乳腺癌细胞系中 HEH可以选择性地吸收到HER2表达细胞中，并成功沉默EGFR基因并下调HER2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表达并抑制肿瘤生长。HEH的治疗功效仅优于HER2适体，这表明HEH通过靶向HER2和EGFR具有协同作用。这项研究表明，HEH作为靶向HER2的新药具有巨大潜力，可以解决当前药物的毒性和耐药性，并且可以为许多HER2阳性癌症提供治愈方法。并抑制肿瘤的生长。HEH的治疗功效仅优于HER2适体，这表明HEH通过靶向HER2和EGFR具有协同作用。这项研究表明，HEH作为靶向HER2的新药物具有巨大潜力，可以解决当前药物的毒性和耐药性，并且可以为许多HER2阳性癌症提供治愈方法。并抑制肿瘤的生长。HEH的治疗功效仅优于HER2适体，这表明HEH通过靶向HER2和EGFR具有协同作用。这项研究表明，HEH作为靶向HER2的新药具有巨大潜力，可以解决当前药物的毒性和耐药性，并且可以为许多HER2阳性癌症提供治愈方法。