Experimental Therapeutics, British Columbia Cancer Agency, 675 West 10th Ave, Vancouver, BC V5Z 1L3, Canada.
BMC Cancer. 2011 Oct 1;11:420. doi: 10.1186/1471-2407-11-420.
HER2-positive breast cancers exhibit high rates of innate and acquired resistance to trastuzumab (TZ), a HER2-directed antibody used as a first line treatment for this disease. TZ resistance may in part be mediated by frequent co-expression of EGFR and by sustained activation of the mammalian target of rapamycin (mTOR) pathway. Here, we assessed feasibility of combining the EGFR inhibitor gefitinib and the mTOR inhibitor everolimus (RAD001) for treating HER2 overexpressing breast cancers with different sensitivity to TZ.
The gefitinib and RAD001 combination was broadly evaluated in TZ sensitive (SKBR3 and MCF7-HER2) and TZ resistant (JIMT-1) breast cancer models. The effects on cell growth were measured in cell based assays using the fixed molar ratio design and the median effect principle. In vivo studies were performed in Rag2M mice bearing established tumors. Analysis of cell cycle, changes in targeted signaling pathways and tumor characteristics were conducted to assess gefitinib and RAD001 interactions.
The gefitinib and RAD001 combination inhibited cell growth in vitro in a synergistic fashion as defined by the Chou and Talalay median effect principle and increased tumor xenograft growth delay. The improvement in therapeutic efficacy by the combination was associated in vitro with cell line dependent increases in cytotoxicity and cytostasis while treatment in vivo promoted cytostasis. The most striking and consistent therapeutic effect of the combination was increased inhibition of the mTOR pathway (in vitro and in vivo) and EGFR signaling in vivo relative to the single drugs.
The gefitinib and RAD001 combination provides effective control over growth of HER2 overexpressing cells and tumors irrespective of the TZ sensitivity status.
HER2 阳性乳腺癌对曲妥珠单抗（TZ）表现出高的先天和获得性耐药，TZ 是一种用于治疗该疾病的 HER2 靶向抗体。TZ 耐药可能部分是由 EGFR 的频繁共表达和哺乳动物雷帕霉素靶蛋白（mTOR）通路的持续激活介导的。在这里，我们评估了联合使用 EGFR 抑制剂吉非替尼和 mTOR 抑制剂依维莫司（RAD001）治疗对 TZ 敏感性不同的 HER2 过表达乳腺癌的可行性。
广泛评估了吉非替尼和 RAD001 联合在 TZ 敏感（SKBR3 和 MCF7-HER2）和 TZ 耐药（JIMT-1）乳腺癌模型中的作用。使用固定摩尔比设计和中值效应原理在基于细胞的测定中测量对细胞生长的影响。在携带已建立肿瘤的 Rag2M 小鼠中进行了体内研究。进行细胞周期分析、靶向信号通路变化和肿瘤特征分析，以评估吉非替尼和 RAD001 的相互作用。
吉非替尼和 RAD001 联合以 Chou 和 Talalay 中值效应原理定义的协同方式抑制体外细胞生长，并增加肿瘤异种移植生长延迟。该组合在体外通过细胞系依赖性增加细胞毒性和细胞停滞来改善治疗效果，而体内治疗则促进细胞停滞。组合最显著和一致的治疗效果是增加对 mTOR 通路（体外和体内）和体内 EGFR 信号的抑制作用，相对于单药治疗。
吉非替尼和 RAD001 联合治疗可有效控制 HER2 过表达细胞和肿瘤的生长，而与 TZ 敏感性状态无关。
