Perhexiline promotes HER3 ablation through receptor internalization and inhibits tumor growth.
Perhexiline promotes HER3 ablation through receptor internalization and inhibits tumor growth.
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DOI：
10.1186/s13058-015-0528-9
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发表时间：
2015-02-15
期刊：
影响因子：
--
通讯作者：
Chen W
中科院分区：
文献类型：
--
作者：
Ren XR;Wang J;Osada T;Mook RA Jr;Morse MA;Barak LS;Lyerly HK;Chen W
人类表皮生长因子受体 HER3 与促进乳腺癌的侵袭性和转移潜力有关。 HER3 的上调已被发现是乳腺癌治疗中对 EGFR 和 HER2 酪氨酸激酶抑制剂以及内分泌治疗产生耐药性的主要机制。因此，减少质膜 HER3 表达的药物可能与当前的疗法产生协同作用，并提供一种新的治疗策略来改善治疗。我们设计了一个基于图像的筛选平台，使用膜定位的 HER3-YFP 来识别促进 HER3 内化和降解的小分子。使用体外和体内肿瘤模型来表征筛选平台鉴定的抗心绞痛药物哌可昔林的信号传导作用。我们发现哌克西林（一种抗心绞痛药物）选择性内化 HER3，降低 HER3 表达，随后抑制 HER3 下游信号传导。与这些结果一致，哌克昔林在体外抑制乳腺癌细胞增殖，在体内抑制肿瘤生长。这是首次证明 HER3 可以通过从细胞膜上消除小分子来靶向。这里使用的新方法发现了 perhexiline 消除了 HER3 表达，并提供了一个机会来确定 HER3 消除调节剂作为创新疗法，以提高乳腺癌患者的生存率。本文的在线版本 (doi:10.1186/s13058-015-0528-9) 包含补充材料，可供授权用户使用。
Human epidermal growth factor receptor HER3 has been implicated in promoting the aggressiveness and metastatic potential of breast cancer. Upregulation of HER3 has been found to be a major mechanism underlying drug resistance to EGFR and HER2 tyrosine kinase inhibitors and to endocrine therapy in the treatment of breast cancer. Thus, agents that reduce HER3 expression at the plasma membrane may synergize with current therapies and offer a novel therapeutic strategy to improve treatment. We devised an image-based screening platform using membrane localized HER3-YFP to identify small molecules that promote HER3 internalization and degradation. In vitro and in vivo tumor models were used to characterize the signaling effects of perhexiline, an anti-anginal drug, identified by the screening platform. We found perhexiline, an anti-anginal drug, selectively internalized HER3, decreased HER3 expression, and subsequently inhibited signaling downstream of HER3. Consistent with these results, perhexiline inhibited breast cancer cell proliferation in vitro and tumor growth in vivo. This is the first demonstration that HER3 can be targeted with small molecules by eliminating it from the cell membrane. The novel approach used here led to the discovery that perhexiline ablates HER3 expression, and offers an opportunity to identify HER3 ablation modulators as innovative therapeutics to improve survival in breast cancer patients. The online version of this article (doi:10.1186/s13058-015-0528-9) contains supplementary material, which is available to authorized users.
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影响因子：
8
作者：
Smirnova, T.;Zhou, Z. N.;Flinn, R. J.;Wyckoff, J.;Boimel, P. J.;Pozzuto, M.;Coniglio, S. J.;Backer, J. M.;Bresnick, A. R.;Condeelis, J. S.;Hynes, N. E.;Segall, J. E.
通讯作者：
Segall, J. E.
影响因子：
9
作者：
Chiu, Connie G.;Masoudi, Hamid;Wiseman, Sam M.
通讯作者：
Wiseman, Sam M.
DOI：
10.2165/00129784-200101030-00005
发表时间：
2001-01-01
期刊：
American journal of cardiovascular drugs : drugs, devices, and other interventions
影响因子：
--
作者：
Killalea, S M;Krum, H
通讯作者：
Krum, H
影响因子：
6.4
作者：
van Agthoven, Ton;Godinho, Marcia F. E.;Dorssers, Lambert C. J.
通讯作者：
Dorssers, Lambert C. J.
影响因子：
11.2
作者：
Schade, Babette;Lam, Sonya H. L.;Muller, William J.
通讯作者：
Muller, William J.