Novel Hsp90 inhibitor FW-04-806 displays potent antitumor effects in HER2-positive breast cancer cells as a single agent or in combination with lapatinib
Novel Hsp90 inhibitor FW-04-806 displays potent antitumor effects in HER2-positive breast cancer cells as a single agent or in combination with lapatinib
复制标题
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。
DOI：
10.1016/j.canlet.2014.10.040
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发表时间：
2015-01-28
期刊：
影响因子：
9.7
通讯作者：
Ye, Min
中科院分区：
文献类型：
--
作者：
Huang, Wei;Wu, Qun-dan;Ye, Min
人表皮生长因子受体2（HER 2）是HER家族酪氨酸激酶的一员，也是热休克蛋白90（Hsp 90）的结合伴侣，在大约25%的乳腺癌中被发现扩增。近年来，HER 2+乳腺癌的治疗已经得到了很大的改善，但是伴随的由HER 2阻断诱导的HER 3上调已经减弱了治疗效果。FW-04-806是一种新型Hsp 90 N-末端抑制剂，可使Hsp 90/Cdc 37/客户端复合物解离并降解Hsp 90客户端，在HER 2+乳腺癌细胞中单独或与EGFR/HER 2酪氨酸激酶抑制剂拉帕替尼联合研究。我们发现，FW-04-806单独或与拉帕替尼一起抑制细胞增殖，诱导细胞凋亡并降低这些细胞中的总HER 3水平和活化HER 3水平，而拉帕替尼已被报道在HER 2抑制后增加HER 3表达。FW-04-806和拉帕替尼联合治疗显示出协同降低HER 2表达和下游PI 3 K/Akt和Ras/MEK/ERIC通路，增强对Akt介导的FOXO 3a失活的抑制，并增强对SKBR 3异种移植物的抗肿瘤疗效，具有良好的毒性特征，表明其作为HER 2+乳腺癌患者临床研究的联合治疗的可行性。(C)2014爱思唯尔爱尔兰有限公司版权所有。
Human epidermal growth factor receptor 2 (HER2), a member of the HER family of tyrosine kinases and a binding partner of Heat shock protein 90 (Hsp90), is found amplifies in approximately 25% breast cancers. Treatment of HER2+ breast cancers has been greatly improved in recent years, but the accompanying upregulation of HER3 induced by HER2 blockade has subdued the therapeutic effect. FW-04-806, a novel Hsp90 N-terminal inhibitor that disassociates the Hsp90/Cdc37/client complex and degrades Hsp90 clients, was studied alone or in combination with the EGFR/HER2 tyrosine kinase inhibitor lapatinib in HER2+ breast cancer cells. We found that FW-04-806 alone or with laptinib inhibits cell proliferation, induces cell apoptosis and reduces the total and activated HER3 levels in these cells, while lapatinib has been reported to increase HER3 expression followed HER2 inhibition. The combination of FW-04-806 and lapatinib showed synergistic reduction of HER2 expression and the downstream PI3K/Akt and Ras/MEK/ERIC pathways, enhanced suppression of Akt-mediated FOXO3a inactivation and augmented antitumor efficacy on SKBR3 xenografts with a favorable toxicity profile, suggesting its viability as a combination therapy for clinical studies in HER2+ breast cancer patients. (C) 2014 Elsevier Ireland Ltd. All rights reserved.