Medical Oncology Department, Vall d'Hebron Institute of Oncology, Barcelona, Spain.
Mol Cancer Ther. 2011 May;10(5):817-24. doi: 10.1158/1535-7163.MCT-10-0966. Epub 2011 Mar 7.
Hsp90 facilitates the maturation and stability of numerous oncoproteins, including HER2. The aim of this study was to assess the antitumor activity of the Hsp90 inhibitor IPI-504 in trastuzumab-resistant, HER2-overexpressing breast cancer cells. Therapy with trastuzumab, IPI-504, and the combination of trastuzumab and IPI-504 was evaluated in trastuzumab-sensitive and trastuzumab-resistant cells. Inhibition of protein targets, cell proliferation, and tumor growth was assessed in vitro and in xenograft models. IPI-504 inhibited proliferation of both trastuzumab-sensitive and trastuzumab-resistant cells. Administration of IPI-504 markedly reduced total levels of HER2 and Akt, as well as phosphorylated Akt and mitogen-activated protein kinase (MAPK), to an equal extent in trastuzumab-sensitive and trastuzumab-resistant cells. IPI-504, used as single agent or in combination with trastuzumab, also inhibited in vivo the growth of both trastuzumab-sensitive and -resistant tumor xenografts. As a mechanism for the observed antitumor activity, IPI-504 resulted in a marked decrease in the levels of HER2, Akt, p-Akt, and p-MAPK in trastuzumab-resistant xenografts as early as 12 hours after a single dose of IPI-504. IPI-504-mediated Hsp90 inhibition may represent a novel therapeutic approach in trastuzumab refractory HER2-positive breast cancer.
Hsp90 促进了许多癌蛋白的成熟和稳定，包括 HER2。本研究旨在评估 Hsp90 抑制剂 IPI-504 在曲妥珠单抗耐药、HER2 过表达乳腺癌细胞中的抗肿瘤活性。在曲妥珠单抗敏感和曲妥珠单抗耐药细胞中评估了曲妥珠单抗、IPI-504 以及曲妥珠单抗和 IPI-504 联合治疗的疗效。在体外和异种移植模型中评估了对蛋白靶标的抑制作用、细胞增殖和肿瘤生长。IPI-504 抑制了曲妥珠单抗敏感和耐药细胞的增殖。IPI-504 的给药显著降低了 HER2 和 Akt 的总水平，以及磷酸化 Akt 和丝裂原活化蛋白激酶（MAPK），在曲妥珠单抗敏感和耐药细胞中达到同等程度。IPI-504 作为单一药物或与曲妥珠单抗联合使用，也抑制了曲妥珠单抗敏感和耐药肿瘤异种移植物的体内生长。作为观察到的抗肿瘤活性的机制，IPI-504 在单次给药后 12 小时内，使曲妥珠单抗耐药异种移植物中的 HER2、Akt、p-Akt 和 p-MAPK 水平显著下降。IPI-504 介导的 Hsp90 抑制可能代表曲妥珠单抗难治性 HER2 阳性乳腺癌的一种新的治疗方法。
