Hsp90 inhibitor PU-H71, a multimodal inhibitor of malignancy, induces complete responses in triple-negative breast cancer models
Hsp90 inhibitor PU-H71, a multimodal inhibitor of malignancy, induces complete responses in triple-negative breast cancer models
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DOI：
10.1073/pnas.0903392106
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发表时间：
2009-05-19
影响因子：
11.1
通讯作者：
Chiosis, Gabriela
中科院分区：
文献类型：
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作者：
Caldas-Lopes, Eloisi;Cerchietti, Leandro;Chiosis, Gabriela
三阴性乳腺癌（TNBC）的定义是缺乏雌激素，孕酮和HER2受体的表达。由于没有确定的靶标和靶向疗法，并且由于分子表现异质，因此针对TNBC患者的治疗指南仅包括常规化学疗法。这种治疗虽然对某些人有效，但其他人的早期复发率很高，对于任何转移性疾病患者均无法治愈。在这里，我们证明这些肿瘤对热休克蛋白90（HSP90）抑制剂PU-H71敏感。 TNBC异种移植物中有效耐用的抗肿瘤作用，包括完全反应和肿瘤回归，对宿主没有毒性，可以使用该药物。值得注意的是，TNBC肿瘤对使用PU-H71的撤退反应，几个循环延伸了5个月以上，而没有耐药性或毒性的证据。通过蛋白质组学方法，我们表明，参与肿瘤增殖，生存和侵入性潜力的多种癌蛋白与TNBC中的PU-H71结合HSP90相对复杂。 PU-H71在体外和体内诱导有效，持续下调和灭活这些蛋白质。其中，我们确定了RAS/RAF/MAPK途径和G（2）-M相的下调，以促进其抗增殖作用，降解活化的Akt和Bcl-XL以诱导凋亡，并抑制活化的NF活化的NF -Kappa B，Akt，Erk2，Tyk2和PKC，以降低TNBC侵入性潜力。结果将HSP90确定为最难治疗乳腺癌亚型的关键和多模式靶标，并支持HSP90抑制剂PU-H71用于涉及TNBC患者的临床试验。
Triple-negative breast cancers (TNBCs) are defined by a lack of expression of estrogen, progesterone, and HER2 receptors. Because of the absence of identified targets and targeted therapies, and due to a heterogeneous molecular presentation, treatment guidelines for patients with TNBC include only conventional chemotherapy. Such treatment, while effective for some, leaves others with high rates of early relapse and is not curative for any patient with metastatic disease. Here, we demonstrate that these tumors are sensitive to the heat shock protein 90 (Hsp90) inhibitor PU-H71. Potent and durable anti-tumor effects in TNBC xenografts, including complete response and tumor regression, without toxicity to the host are achieved with this agent. Notably, TNBC tumors respond to retreatment with PU-H71 for several cycles extending for over 5 months without evidence of resistance or toxicity. Through a proteomics approach, we show that multiple oncoproteins involved in tumor proliferation, survival, and invasive potential are in complex with PU-H71-bound Hsp90 in TNBC. PU-H71 induces efficient and sustained downregulation and inactivation, both in vitro and in vivo, of these proteins. Among them, we identify downregulation of components of the Ras/Raf/MAPK pathway and G(2)-M phase to contribute to its anti-proliferative effect, degradation of activated Akt and Bcl-xL to induce apoptosis, and inhibition of activated NF-kappa B, Akt, ERK2, Tyk2, and PKC to reduce TNBC invasive potential. The results identify Hsp90 as a critical and multimodal target in this most difficult to treat breast cancer subtype and support the use of the Hsp90 inhibitor PU-H71 for clinical trials involving patients with TNBC.