Inhibition of mammalian target of rapamycin is required for optimal antitumor effect of HER2 inhibitors against HER2-overexpressing cancer cells.
Inhibition of mammalian target of rapamycin is required for optimal antitumor effect of HER2 inhibitors against HER2-overexpressing cancer cells.
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DOI：
10.1158/1078-0432.ccr-09-1665
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发表时间：
2009-12-01
期刊：
影响因子：
--
通讯作者：
Arteaga CL
中科院分区：
文献类型：
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作者：
Miller TW;Forbes JT;Shah C;Wyatt SK;Manning HC;Olivares MG;Sanchez V;Dugger TC;de Matos Granja N;Narasanna A;Cook RS;Kennedy JP;Lindsley CW;Arteaga CL
在HER2过表达的乳腺癌中，有相当一部分对HER2抗体曲妥珠单抗表现出耐药性。磷脂酰肌醇-3激酶(PI3K)/AKT通路的高活性导致曲妥珠单抗耐药，而mTOR是PI3K/AKT的主要下游效应因子。因此，我们研究了mTOR抑制剂是否与曲妥珠单抗有协同作用。携带HER2阳性乳腺肿瘤的免疫活性小鼠接受曲妥珠单抗、mTOR抑制剂雷帕霉素或其组合治疗。使用光学Annexin-V探针和[18F]FDG-PET对小鼠的肿瘤细胞死亡进行成像。观察mTOR抑制剂RAD001对曲妥珠单抗或拉帕替尼处理的HER2+细胞的信号和生长的影响。曲妥珠单抗加雷帕霉素对小鼠的治疗比单一药物治疗更有效，导致26/26肿瘤完全消退。联合应用可诱导肿瘤细胞死亡(Annexin-V结合)并抑制FDG摄取。分别用磷酸化S6和Ki67免疫组织化学方法检测雷帕霉素抑制mTOR和肿瘤细胞增殖。在培养中，RAD001和曲妥珠单抗联合使用比单独使用任何一种药物都更有效地抑制细胞生长。曲妥珠单抗可部分降低PI3K活性，但不降低mTOR活性。TSC2基因敲除导致mTOR的HER2非依赖性激活，并抑制曲妥珠单抗和拉帕替尼的反应。用HER2抑制剂拉帕替尼处理后，表达TSC2的细胞中的磷酸化S6和生长减少，但在TSC2基因敲除的细胞中没有。HER2拮抗剂的生长抑制作用需要抑制PI3K和mTOR。这些发现共同支持曲妥珠单抗和mTOR抑制剂联合用于HER2+乳腺癌的治疗。
A significant fraction of HER2-overexpressing breast cancers exhibit resistance to the HER2 antibody trastuzumab. Hyperactivity of the phosphatidylinositol-3 kinase (PI3K)/AKT pathway confers trastuzumab resistance, and mTOR is a major downstream effector of PI3K/AKT. Therefore, we examined whether mTOR inhibitors synergize with trastuzumab. Immunocompetent mice bearing HER2-positive mammary tumors were treated with trastuzumab, the mTOR inhibitor rapamycin, or the combination. Mice were imaged for tumor cell death using an optical Annexin-V probe and with [18F]FDG-PET. The signaling and growth effects of the mTOR inhibitor RAD001 on HER2+ cells treated with trastuzumab or lapatinib were evaluated. Treatment of mice with trastuzumab plus rapamycin was more effective than single-agent treatments, inducing complete regression of 26/26 tumors. The combination induced tumor cell death (Annexin-V binding) and inhibited FDG uptake. Rapamycin inhibited mTOR and tumor cell proliferation as determined by phospho-S6 and Ki67 immunohistochemistry, respectively. In culture, the combination of RAD001 plus trastuzumab inhibited cell growth more effectively than either drug alone. Trastuzumab partially decreased PI3K but not mTOR activity. Knockdown of TSC2 resulted in HER2-independent activation of mTOR and dampened the response to trastuzumab and lapatinib. Treatment with the HER2 inhibitor lapatinib decreased phospho-S6 and growth in TSC2-expressing but not in TSC2-knockdown cells. Inhibition of PI3K and mTOR are required for the growth inhibitory effect of HER2 antagonists. These findings collectively support the combined use of trastuzumab and mTOR inhibitors for the treatment of HER2+ breast cancer.