EGFR blockade enriches for lung cancer stem-like cells through Notch3-dependent signaling.
EGFR blockade enriches for lung cancer stem-like cells through Notch3-dependent signaling.
复制标题
EGFR阻断通过Notch3依赖性信号传导富集了肺癌干细胞。
DOI：
10.1158/0008-5472.can-13-3724
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发表时间：
2014-10-01
期刊：
影响因子：
11.2
通讯作者：
Carbone DP
中科院分区：
文献类型：
--
作者：
Arasada RR;Amann JM;Rahman MA;Huppert SS;Carbone DP
表皮生长因子受体（EGFR）突变是肺癌中最常见的可操作的遗传异常。然而，用激酶抑制剂靶向这些突变不能治愈晚期疾病，并且尚未证明对潜在可治愈的早期疾病的影响，一些数据表明不良结果。在这里，我们报告了用厄洛替尼治疗EGFR突变的肺癌细胞系，虽然显示出强大的细胞死亡，但通过EGFR依赖性Notch3激活来富集ALDH+干细胞样细胞。此外，我们证明，厄洛替尼治疗增加肺癌细胞的克隆形成在一个球体形成试验，表明增加干细胞样细胞的潜力。我们证明，EGFR激酶活性的抑制导致Notch转录靶点以γ分泌酶抑制剂敏感的方式激活，并导致Notch激活。导致ALDH高+细胞的增加。我们还发现了Notch3和EGFR受体与Notch3酪氨酸磷酸化之间的激酶依赖性物理关联。这可以解释在一些厄洛替尼治疗早期疾病的研究中观察到的生存率恶化，并表明特异性双重靶向可能克服这种不良反应。
Mutations in the epidermal growth factor receptor (EGFR) are the most common actionable genetic abnormalities yet discovered in lung cancer. However, targeting these mutations with kinase inhibitors is not curative in advanced disease and has yet to demonstrate an impact on potentially curable, early-stage disease, with some data suggesting adverse outcomes. Here, we report that treatment of EGFR-mutated lung cancer cell lines with erlotinib, while showing robust cell death, enriches the ALDH+ stem-like cells through EGFR-dependent activation of Notch3. Additionally, we demonstrate that erlotinib treatment increases the clonogenicity of lung cancer cells in a sphere-forming assay, suggesting increased stem-like cell potential. We demonstrate that inhibition of EGFR kinase activity leads to activation of Notch transcriptional targets in a gamma secretase inhibitor sensitive manner and causes Notch activation. leading to an increase in ALDH high+ cells. We also find a kinase-dependent physical association between the Notch3 and EGFR receptors and tyrosine phosphorylation of Notch3. This could explain the worsened survival observed in some studies of erlotinib treatment at early-stage disease, and suggests that specific dual targeting might overcome this adverse effect.