Department of Medical Oncology, Kinki University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka 589-8511, Japan.
Br J Cancer. 2012 Feb 14;106(4):763-7. doi: 10.1038/bjc.2011.586. Epub 2012 Jan 12.
Although most non-small-cell lung cancer (NSCLC) patients with the echinoderm microtubule-associated protein-like 4 (EML4) - anaplastic lymphoma kinase (ALK) fusion gene - benefit from ALK tyrosine kinase inhibitors (ALK-TKIs), the efficacy of these drugs varies greatly among individuals.
The antitumour action of ALK-TKIs in EML4-ALK-positive NSCLC cell lines was evaluated from their effects on cell proliferation, signal transduction, and apoptosis.
The ALK-TKI TAE684 inhibited cell proliferation and induced apoptosis, in association with inhibition of STAT3 and ERK phosphorylation, in EML4-ALK-positive H3122 cells. TAE684 inhibited STAT3 phosphorylation, but not ERK phosphorylation, and it showed little effect on cell proliferation or apoptosis, in EML4-ALK-positive H2228 cells. The combination of TAE684 and a MEK inhibitor-induced marked apoptosis accompanied by inhibition of STAT3 and ERK pathways in H2228 cells. Such dual interruption of STAT3 and ERK pathways induced downregulation of the antiapoptotic protein survivin and upregulation of the proapoptotic protein BIM.
Our results indicate that interruption of both STAT3-survivin and ERK-BIM pathways is required for induction of apoptosis in NSCLC harbouring EML4-ALK, providing a rationale for combination therapy with ALK and MEK inhibitors in EML4-ALK-positive NSCLC patients for whom ALK inhibitors alone are ineffective.
虽然大多数携带有棘皮动物微管相关蛋白样 4（EML4）-间变性淋巴瘤激酶（ALK）融合基因的非小细胞肺癌（NSCLC）患者受益于 ALK 酪氨酸激酶抑制剂（ALK-TKIs），但这些药物在个体间的疗效差异很大。
通过观察对细胞增殖、信号转导和细胞凋亡的影响来评估 ALK-TKIs 在 EML4-ALK 阳性 NSCLC 细胞系中的抗肿瘤作用。
ALK-TKI TAE684 抑制 EML4-ALK 阳性 H3122 细胞的增殖并诱导其凋亡，同时抑制 STAT3 和 ERK 的磷酸化。TAE684 抑制 STAT3 的磷酸化，但不抑制 ERK 的磷酸化，对 EML4-ALK 阳性 H2228 细胞的增殖和凋亡几乎没有影响。TAE684 与 MEK 抑制剂联合使用可显著诱导 H2228 细胞凋亡，并抑制 STAT3 和 ERK 通路。这种双重阻断 STAT3 和 ERK 通路可下调抗凋亡蛋白 survivin 并上调促凋亡蛋白 BIM。
我们的研究结果表明，ALK 抑制剂治疗无效的 EML4-ALK 阳性 NSCLC 患者需要同时阻断 STAT3-survivin 和 ERK-BIM 通路以诱导细胞凋亡，为 ALK 和 MEK 抑制剂联合治疗提供了理论依据。
