Lack of acquired resistance in HER2-positive breast cancer cells after long-term HER2 siRNA nanoparticle treatment.
Lack of acquired resistance in HER2-positive breast cancer cells after long-term HER2 siRNA nanoparticle treatment.
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DOI：
10.1371/journal.pone.0198141
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发表时间：
2018
期刊：
影响因子：
3.7
通讯作者：
Yantasee W
中科院分区：
文献类型：
--
作者：
Gu S;Ngamcherdtrakul W;Reda M;Hu Z;Gray JW;Yantasee W
对当前HER2靶向治疗的内在和获得性耐药在临床上仍然是一个挑战。我们开发了一种治疗性的HER2 siRNA，它使用介孔二氧化硅纳米颗粒修饰聚合物并与HER2靶向抗体偶联。我们之前的研究表明，我们的HER2 siRNA纳米颗粒可以克服HER2阳性乳腺癌患者对曲妥珠单抗和拉帕替尼的内在和获得性耐药性。在这项研究中，我们使用我们的治疗性HER2 siRNA研究了长期(7个月)治疗的效果。即使在去除HER2 siRNA后，长期处理的细胞生长速度也比未接受任何处理的细胞慢得多(倍增时间增加67%)。处理后的细胞没有发生上皮-间充质转化，也没有表现出肿瘤起始细胞的浓缩。与曲妥珠单抗和拉帕替尼在治疗6个月后诱导BT474细胞耐药不同，HER2 siRNA不会诱导对HER2 siRNA、曲妥珠单抗或拉帕替尼的耐药性。用HER2 siRNA消融HER2可阻止在对拉帕替尼耐药的细胞中观察到的HER2信号的重新激活。总之，我们的结果表明，基于HER2 siRNA的治疗性药物在体外对HER2信号提供了更持久的抑制，并且可能比现有的治疗性单抗和小分子抑制剂更有效。
Intrinsic and acquired resistance to current HER2 targeted therapies remains a challenge in clinics. We have developed a therapeutic HER2 siRNA delivered using mesoporous silica nanoparticles modified with polymers and conjugated with HER2 targeting antibodies. Our previous studies have shown that our HER2 siRNA nanoparticles could overcome intrinsic and acquired resistance to trastuzumab and lapatinib in HER2-positive breast cancers. In this study, we investigated the effect of long-term (7 months) treatment using our therapeutic HER2 siRNA. Even after the removal of HER2 siRNA, the long-term treated cells grew much slower (67% increase in doubling time) than cells that have not received any treatment. The treated cells did not undergo epithelial-mesenchymal transition or showed enrichment of tumor initiating cells. Unlike trastuzumab and lapatinib, which induced resistance in BT474 cells after 6 months of treatment, HER2 siRNA did not induce resistance to HER2 siRNA, trastuzumab, or lapatinib. HER2 ablation with HER2 siRNA prevented reactivation of HER2 signaling that was observed in cells resistant to lapatinib. Altogether, our results indicate that a HER2 siRNA based therapeutic provides a more durable inhibition of HER2 signaling in vitro and can potentially be more effective than the existing therapeutic monoclonal antibodies and small molecule inhibitors.
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影响因子：
5.7
作者：
Morry J;Ngamcherdtrakul W;Gu S;Reda M;Castro DJ;Sangvanich T;Gray JW;Yantasee W
通讯作者：
Yantasee W
DOI：
10.1200/jco.2016.67.4887
发表时间：
2017-01-10
期刊：
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
影响因子：
--
作者：
Perez EA;Barrios C;Eiermann W;Toi M;Im YH;Conte P;Martin M;Pienkowski T;Pivot X;Burris H 3rd;Petersen JA;Stanzel S;Strasak A;Patre M;Ellis P
通讯作者：
Ellis P
影响因子：
4.3
作者：
Canfield, Kaleigh;Li, Jiaqi;Kurokawa, Manabu
通讯作者：
Kurokawa, Manabu
影响因子：
6.2
作者：
Henjes, F.;Bender, C.;von der Heyde, S.;Braun, L.;Mannsperger, H. A.;Schmidt, C.;Wiemann, S.;Hasmann, M.;Aulmann, S.;Beissbarth, T.;Korf, U.
通讯作者：
Korf, U.
影响因子：
28.2
作者：
Bose R;Kavuri SM;Searleman AC;Shen W;Shen D;Koboldt DC;Monsey J;Goel N;Aronson AB;Li S;Ma CX;Ding L;Mardis ER;Ellis MJ
通讯作者：
Ellis MJ