非小細(xì)胞肺癌（Non-small-cell carcinoma ）包括鱗癌、腺癌,、大細(xì)胞癌,，與小細(xì)胞癌相比其癌細(xì)胞生長分裂較慢，擴散轉(zhuǎn)移相對較晚,，約占肺癌總敉的80-85%,。
近日，BJC（British Journal of Cancer）發(fā)表了日本近畿大學(xué)醫(yī)學(xué)院和達納法伯癌癥研究所研究人員在非小細(xì)胞肺癌領(lǐng)域的研究成果,。
大多數(shù)的非小細(xì)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酪氨酸激酶抑制劑（ALK-TKIs）治療,，但是這類藥物的治療效果卻有很大的個體差異,。
研究發(fā)現(xiàn)，ALK-TKI TAE684可以抑制EML4-ALK-positive H3122細(xì)胞增殖,、誘導(dǎo)其凋亡,，因其可以抑制STAT3和ERK磷酸化。而TAE684能夠阻止EML4-ALK-positive H2228 細(xì)胞的STAT3磷酸化,，但不能阻斷ERK磷酸化,，對于細(xì)胞增殖或凋亡也無顯著作用。
MEK抑制劑可使H2228細(xì)胞發(fā)生凋亡，若同時使用TAE684,，那么STAT3和ERK途徑都受到抑制,。STAT3和ERK途徑阻斷后，抗凋亡蛋白survivin將會下調(diào),，而促凋亡蛋白BIM則上調(diào),。
研究結(jié)果表明，對于有EML4-ALK融合基因的非小細(xì)胞肺癌,，同時阻斷STAT3-survivin和ERK-BIM途徑才能誘導(dǎo)細(xì)胞的凋亡,。由此，對于單獨ALK抑制劑不能發(fā)揮治療作用的EML4-ALK-positive非小細(xì)胞肺癌患者,，可以同時使用ALK和MEK抑制劑,。（生物谷Bioon.com）
doi:10.1038/bjc.2011.586
PMC:
PMID:
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.
