Ganetespib targets multiple levels of the receptor tyrosine kinase signaling cascade and preferentially inhibits ErbB2-overexpressing breast cancer cells.
Ganetespib targets multiple levels of the receptor tyrosine kinase signaling cascade and preferentially inhibits ErbB2-overexpressing breast cancer cells.
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DOI：
10.1038/s41598-018-25284-0
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发表时间：
2018-05-01
影响因子：
4.6
通讯作者：
Yang X
中科院分区：
文献类型：
--
作者：
Lee H;Saini N;Howard EW;Parris AB;Ma Z;Zhao Q;Zhao M;Liu B;Edgerton SM;Thor AD;Yang X
尽管ErbB2靶向治疗显著改善了ErbB2+乳腺癌患者的预后，但治疗耐药性仍然是一个重大挑战。因此，开发新的ErbB2靶向策略是必要的。重要的是，ErbB2是热休克蛋白90(HSP90)的敏感客户蛋白，它调节客户蛋白的折叠、成熟和稳定。抑制HSP90为ErbB2靶向降解提供了另一种治疗策略。特别是，一种新型的HSP90抑制剂Ganetespib是治疗ErbB2+癌症的有前途的药物。然而，Ganetespib对ErbB2+乳腺癌的抗癌效果和临床应用尚不清楚。在我们的研究中，我们检测了Ganetespib对ErbB2+BT474和SKBR3乳腺癌细胞以及慢病毒介导的ErbB2过表达的等基因配对癌细胞的抗癌作用。Ganetespib有效地抑制了ErbB2+乳腺癌细胞的细胞增殖、细胞周期进程、存活以及ErbB2及其关键下游效应分子的激活/磷酸化。此外，Ganetespib还降低了HSP90客户蛋白的总蛋白水平，并缩短了ErbB2蛋白的半衰期。ERBB2过表达的癌细胞对Ganetespib介导的生长抑制也比亲本细胞更敏感。Ganetespib还显著增强了拉帕替尼对BT474和SKBR3细胞的抑制作用。最终，我们的结果支持了Ganetespib介导的HSP90抑制作为ErbB2+乳腺癌的一种有前途的治疗策略的应用。
Although ErbB2-targeted therapeutics have significantly improved ErbB2+ breast cancer patient outcomes, therapeutic resistance remains a significant challenge. Therefore, the development of novel ErbB2-targeting strategies is necessary. Importantly, ErbB2 is a sensitive client protein of heat shock protein 90 (HSP90), which regulates client protein folding, maturation, and stabilization. HSP90 inhibition provides an alternative therapeutic strategy for ErbB2-targeted degradation. In particular, ganetespib, a novel HSP90 inhibitor, is a promising agent for ErbB2+ cancers. Nevertheless, the anti-cancer efficacy and clinical application of ganetespib for ErbB2+ breast cancer is largely unknown. In our study, we examined the anti-cancer effects of ganetespib on ErbB2+ BT474 and SKBR3 breast cancer cells, and isogenic paired cancer cell lines with lentivirus-mediated ErbB2 overexpression. Ganetespib potently inhibited cell proliferation, cell cycle progression, survival, and activation/phosphorylation of ErbB2 and key downstream effectors in ErbB2+ breast cancer cells. Moreover, ganetespib decreased the total protein levels of HSP90 client proteins and reduced ErbB2 protein half-life. ErbB2-overexpressing cancer cells were also more sensitive to ganetespib-mediated growth inhibition than parental cells. Ganetespib also strikingly potentiated the inhibitory effects of lapatinib in BT474 and SKBR3 cells. Ultimately, our results support the application of ganetespib-mediated HSP90 inhibition as a promising therapeutic strategy for ErbB2+ breast cancer.
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DOI：
10.1186/s13058-017-0879-5
发表时间：
2017-08-02
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Jhaveri K;Wang R;Teplinsky E;Chandarlapaty S;Solit D;Cadoo K;Speyer J;D'Andrea G;Adams S;Patil S;Haque S;O'Neill T;Friedman K;Esteva FJ;Hudis C;Modi S
通讯作者：
Modi S
新型 Hsp90 抑制剂 FW-04-806 作为单一药物或与拉帕替尼联合使用，在 HER2 阳性乳腺癌细胞中显示出有效的抗肿瘤作用。
影响因子：
9.7
作者：
Huang, Wei;Wu, Qun-dan;Ye, Min
通讯作者：
Ye, Min
影响因子：
8
作者：
通讯作者：
--
影响因子：
3.4
作者：
Proia, David A.;Sang, Jim;He, Suqin;Smith, Donald L.;Sequeira, Manuel;Zhang, Chaohua;Liu, Yuan;Ye, Shuxia;Zhou, Dan;Blackman, Ronald K.;Foley, Kevin P.;Koya, Keizo;Wada, Yumiko
通讯作者：
Wada, Yumiko
DOI：
10.1158/1078-0432.ccr-11-1218
发表时间：
2011-08-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Arteaga CL
通讯作者：
Arteaga CL