Targeted delivery of CD44s-siRNA by ScFv overcomes de novo resistance to cetuximab in triple negative breast cancer
Targeted delivery of CD44s-siRNA by ScFv overcomes de novo resistance to cetuximab in triple negative breast cancer
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ScFv 靶向递送 CD44s-siRNA 克服了三阴性乳腺癌对西妥昔单抗的从头耐药性
DOI：
10.1016/j.molimm.2018.05.010
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发表时间：
2018-07-01
影响因子：
3.6
通讯作者：
Jin, Wei
中科院分区：
文献类型：
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作者：
Fu, Wenyan;Sun, Hefen;Jin, Wei
EGFR过表达常见于TNBC，抗EGFR受体抗体西妥昔单抗在临床上广泛用于治疗转移性癌。然而，针对TNBC的egfr靶向疗法尚未取得临床成功。在这项研究中，我们发现受损的EGFR降解对西妥昔单抗的耐药性至关重要，这取决于细胞表面分子CD44。为了进一步研究CD44在EGFR信号传导中的作用及其治疗潜力，我们开发了一种靶向融合蛋白，由西妥昔单抗和截断的鱼精蛋白合成的抗EGFR scFv组成，称为Ce-tP。CD44 siRNA可以通过Ce-tP特异性递送到egfr阳性TNBC细胞中。在EGFR阳性的TNBC细胞中观察到CD44的有效敲除和Ce-tP/siRNA复合物对EGFR和下游信号的抑制。更重要的是，我们的研究结果还表明，靶向递送CD44特异性siRNA可以有效地克服体外和体内TNBC细胞对EGFR靶向的抗性。总之，我们的研究结果建立了在TNBC中实现EGFR抑制和限制耐药的新原理。
The overexpression of EGFR often occurs in TNBC, and the anti-EGFR receptor antibody cetuximab is used widely to treat metastatic cancer in the clinic. However, EGFR-targeted therapies have been developed for TNBC without clinical success. In this study, we show that impaired EGFR degradation is crucial for resistance to cetuximab, which depends on the cell surface molecule CD44. To further investigate the role of CD44 in EGFR signaling and its treatment potential, we developed a targeting fusion protein composed of an anti-EGFR scFv generated from cetuximab and truncated protamine, called Ce-tP. CD44 siRNA can be specifically delivered into EGFR-positive TNBC cells by Ce-tP. Efficient knockdown of CD44 and suppression of both EGFR and downstream signaling by the Ce-tP/siRNA complex were observed in EGFR-positive TNBC cells. More importantly, our results also showed that targeted delivery of siRNA specific for CD44 can efficiently overcome resistance to EGFR targeting in TNBC cells both in vitro and in vivo. Overall, our results establish a new principle to achieve EGFR inhibition in TNBC and limit drug resistance.