Yang Lin, Li Guangchao, Zhao Likun, Pan Fei, Qiang Jiankun, Han Siqi
Department of Clinical Laboratory, Hubei Maternal and Child Health Hospital, Wuhan, 430070, China.
Tumour Biol. 2014 Oct;35(10):9759-67. doi: 10.1007/s13277-014-2252-y. Epub 2014 Jun 29.
Targeted therapy based on ALK tyrosine kinase inhibitors (ALK-TKIs) has made significant achievements in individuals with EML4-ALK (echinoderm microtubule-associated protein-like 4 gene and the anaplastic lymphoma kinase gene) fusion positive nonsmall-cell lung cancer (NSCLC). However, a high fraction of patients receive inferior clinical response to such treatment in the initial therapy, and the exact mechanisms underlying this process need to be further investigated. In this study, we revealed a persistently activated PI3K/AKT signaling that mediates the drug ineffectiveness. We found that genetic or pharmacological inhibition of ALK markedly abrogated phosphorylated STAT3 and ERK, but it failed to suppress AKT activity or induce apoptosis, in EML4-ALK-positive H2228 cells. Furthermore, targeted RNA interference of PI3K pathway components restored sensitivity to TAE684 treatment at least partially due to increased apoptosis. Combined TAE684 with PI3K inhibitor synergistically inhibited the proliferation of EML4-ALK-positive cells in vitro and significantly suppressed the growth of H2228 xenografts in vivo, suggesting the potential clinical application of such combinatorial therapy regimens in patients with EML4-ALK positive lung cancer.
基于间变性淋巴瘤激酶酪氨酸激酶抑制剂（ALK-TKIs）的靶向治疗在棘皮动物微管相关蛋白样4基因（EML4）-ALK（间变性淋巴瘤激酶基因）融合阳性的非小细胞肺癌（NSCLC）患者中取得了显著成效。然而，很大一部分患者在初始治疗中对这种治疗的临床反应较差，这一过程背后的确切机制需要进一步研究。在本研究中，我们揭示了一种持续激活的PI3K/AKT信号传导，它介导了药物无效。我们发现，在EML4-ALK阳性的H2228细胞中，对ALK进行基因或药理学抑制可显著消除磷酸化的STAT3和ERK，但无法抑制AKT活性或诱导细胞凋亡。此外，对PI3K途径成分进行靶向RNA干扰至少部分恢复了对TAE684治疗的敏感性，这是由于细胞凋亡增加所致。将TAE684与PI3K抑制剂联合使用可在体外协同抑制EML4-ALK阳性细胞的增殖，并在体内显著抑制H2228异种移植瘤的生长，这表明这种联合治疗方案在EML4-ALK阳性肺癌患者中具有潜在的临床应用价值。
