Inhibitors of HSP90 block p95-HER2 signaling in Trastuzumab-resistant tumors and suppress their growth.
Inhibitors of HSP90 block p95-HER2 signaling in Trastuzumab-resistant tumors and suppress their growth.
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HSP90 抑制剂可阻断曲妥珠单抗耐药肿瘤中的 p95-HER2 信号传导并抑制其生长。
DOI：
10.1038/onc.2009.337
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发表时间：
2010-01-21
期刊：
影响因子：
8
通讯作者：
Rosen, N.
中科院分区：
文献类型：
--
作者：
Chandarlapaty, S.;Scaltriti, M.;Angelini, P.;Ye, Q.;Guzman, M.;Hudis, C. A.;Norton, L.;Solit, D. B.;Arribas, J.;Baselga, J.;Rosen, N.
抗HER 2抗体曲妥珠单抗（赫赛汀）已被证明在治疗HER 2过表达乳腺癌中有效;然而，耐药性总是出现在转移性肿瘤中。p95-HER 2的表达是一种缺乏曲妥珠单抗结合表位的截短细胞外结构域的HER 2形式，被认为是对抗体耐药的机制。我们利用过表达p95-HER 2的体内肿瘤模型，并证明其对曲妥珠单抗的信号传导和抗肿瘤作用具有抗性。我们发现，全长和p95-HER 2与HSP 90伴侣蛋白相互作用，并在组织培养和体内暴露于HSP 90抑制剂的肿瘤细胞中降解。p95-HER 2表达的缺失伴随着PI 3 K/AKT和ERK信号传导途径的下调以及细胞增殖的抑制。在曲妥珠单抗耐药、p95-HER 2过表达模型中，体内长期给予HSP 90抑制剂可导致HER 2和p95-HER 2表达持续丧失，抑制AKT活化，同时诱导细胞凋亡，并完全抑制肿瘤生长。因此，p95-HER 2是一种HSP 90客户蛋白，其表达和功能可以在体内被HSP 90抑制剂有效抑制。因此，HSP 90抑制是p95-HER 2介导的曲妥珠单抗耐药乳腺癌的潜在有效治疗策略。
The anti-HER2 antibody Trastuzumab (Herceptin) has been proven to be effective in the treatment of HER2 overexpressing breast cancer; resistance, however invariably emerges in metastatic tumors. The expression of p95-HER2, a form of HER2 with a truncated extracellular domain that lacks the Trastuzumab binding epitope, has been implicated as a mechanism of resistance to the antibody. We utilized an in vivo tumor model that overexpresses p95-HER2 and demonstrate it to be resistant to the signaling and antitumor effects of Trastuzumab. We find that both full length and p95-HER2 interact with the HSP90 chaperone protein and are degraded in tumor cells exposed to HSP90 inhibitors in tissue culture and in vivo. Loss of expression of p95-HER2 is accompanied by downregulation of the PI3K/AKT and ERK signaling pathways and inhibition of cell proliferation. Chronic administration of HSP90 inhibitors in vivo results in sustained loss of HER2 and p95-HER2 expression and inhibition of AKT activation together with induction of apoptosis and complete inhibition of tumor growth in Trastuzumab-resistant, p95-HER2-overexpressing models. Thus, p95-HER2 is an HSP90 client protein, the expression and function of which can be effectively suppressed in vivo by HSP90 inhibitors. HSP90 inhibition is therefore a potentially effective therapeutic strategy for p95-HER2-mediated Trastuzumab-resistant breast cancer.
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