Combined MEK and EGFR inhibition demonstrates synergistic activity in EGFR-dependent NSCLC
Combined MEK and EGFR inhibition demonstrates synergistic activity in EGFR-dependent NSCLC
复制标题
DOI：
10.4161/cbt.8.6.7690
复制
发表时间：
2009-03-15
影响因子：
3.6
通讯作者：
Black, Esther P.
中科院分区：
文献类型：
--
作者：
Balko, Justin M.;Jones, Brett R.;Black, Esther P.
表皮生长因子受体（EGFR）抑制剂在治疗表达活化EGFR的非小细胞肺癌（NSCLC），尤其是携带EGFR突变的肺癌方面非常有效。然而，大多数受益于EGFR抑制剂的患者仅获得部分缓解或病情稳定，这促进了耐药性的产生。因此，有反应的患者的无进展生存期优势并不显著。联合治疗，最好使用具有协同活性的药物，既可以提高疗效，又可以降低获得性耐药率。我们假设将MEK抑制剂与EGFR抑制剂联合使用可能会产生这样的益处。MAPK通路位于EGFR下游，在多种癌症类型中传递增殖和存活信号。该通路的抑制剂目前正在进行临床试验，但几乎没有证据支持在依赖EGFR的NSCLC中将这些药物作为单一疗法使用。在这项研究中，我们发现依赖EGFR的NSCLC细胞系对ERK1/2活性的丧失具有中等敏感性，无论是通过小分子抑制还是通过siRNA敲低。抑制的结果取决于培养基的营养成分，在富含血清的条件下主要是抗增殖作用，在缺乏血清的条件下是促凋亡作用。然而，当MEK抑制与EGFR抑制剂联合使用时，在含血清的培养基中测试的所有依赖EGFR的细胞系都观察到了细胞毒性协同作用。在有和没有EGFR突变的细胞系中，包括那些携带T790M耐药突变的细胞系，都显示出细胞毒性增强。这些发现支持未来将针对EGFR和MEK1/2的药物联合进行临床研究，以调查在临床筛选的依赖EGFR的NSCLC中是否可以实现更好的治疗效果。
Epidermal growth factor receptor (EGFR) inhibitors are highly effective in treating non-small cell lung cancers (NSCLC) expressing activated EGFR, particularly those harboring EGFR mutations. However, most patients who benefit from EGFR inhibitors achieve only partial responses or stable disease, facilitating the emergence of resistance. Thus, progression-free survival advantages in responding patients are modest. Combination therapy, preferably using agents with synergistic activity, could both improve responses and reduce acquired resistance rates. We hypothesized that combining MEK inhibitors with EGFR inhibitors could result in such a benefit. The MAPK pathway lies downstream of EGFR and transduces both proliferative and survival signals in a variety of cancer types. Inhibitors of this pathway are currently in clinical trials, but little evidence exists supporting the use of these agents as monotherapy in EGFR-dependent NSCLC. In this study, we find EGFR-dependent NSCLC cell lines are moderately sensitive to loss of ERK1/2 activity, either by small molecule inhibition or by siRNA knockdown. The consequence of inhibition is dependent upon the trophic content of the culture media, primarily anti-proliferative in serum-rich conditions and pro-apoptotic in serum-poor conditions. However, when MEK inhibition was combined with EGFR inhibitors, cytotoxic synergy was observed for all EGFR-dependent cell lines tested in serum-containing media. Enhanced cytotoxicity is demonstrated in cell lines with and without EGFR mutations, including those harboring the T790M escape mutation. These findings support future clinical studies that combine EGFR-and MEK1/2-targeted agents to investigate whether improved outcomes can be achieved in clinically screened EGFR-dependent NSCLC.