非小细胞肺癌（Non-small-cell carcinoma ）包括鳞癌、腺癌、大细胞癌，与小细胞癌相比其癌细胞生长分裂较慢，扩散转移相对较晚，约占肺癌总敉的80-85%。
近日，BJC（British Journal of Cancer）发表了日本近畿大学医学院和达纳法伯癌症研究所研究人员在非小细胞肺癌领域的研究成果。
大多数的非小细胞肺癌（NSCLC，non-small-cell lung cancer）患者都有EML4（echinoderm microtubule-associated protein-like 4）和ALK（anaplastic lymphoma kinase）融合基因，因此可以用ALK酪氨酸激酶抑制剂（ALK-TKIs）治疗，但是这类药物的治疗效果却有很大的个体差异。
研究发现，ALK-TKI TAE684可以抑制EML4-ALK-positive H3122细胞增殖、诱导其凋亡，因其可以抑制STAT3和ERK磷酸化。而TAE684能够阻止EML4-ALK-positive H2228 细胞的STAT3磷酸化，但不能阻断ERK磷酸化，对于细胞增殖或凋亡也无显著作用。
MEK抑制剂可使H2228细胞发生凋亡，若同时使用TAE684，那么STAT3和ERK途径都受到抑制。STAT3和ERK途径阻断后，抗凋亡蛋白survivin将会下调，而促凋亡蛋白BIM则上调。
研究结果表明，对于有EML4-ALK融合基因的非小细胞肺癌，同时阻断STAT3-survivin和ERK-BIM途径才能诱导细胞的凋亡。由此，对于单独ALK抑制剂不能发挥治疗作用的EML4-ALK-positive非小细胞肺癌患者，可以同时使用ALK和MEK抑制剂。（生物谷Bioon.com）
doi:10.1038/bjc.2011.586
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Combined effect of ALK and MEK inhibitors in EML4–ALK-positive non-small-cell lung cancer cells
J Tanizaki, I Okamoto1, K Takezawa, K Sakai1, K Azuma, K Kuwata1, H Yamaguchi, E Hatashita, K Nishio, P A Janne and K Nakagawa
Background: 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.
Methods: 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.
Results: 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.
Conclusion: 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.
