Role of ERK-BIM and STAT3-Survivin Signaling Pathways in ALK Inhibitor-Induced Apoptosis in EML4-ALK-Positive Lung Cancer

摘要: Purpose: EML4-ALK (echinoderm microtubule-associated protein–like 4 anaplastic lymphoma kinase) was recently identified as a transforming fusion gene in non–small cell lung cancer. The purpose of the present study to characterize mechanism malignant transformation by EML4-ALK. Experimental Design: We established NIH 3T3 cells that stably express variant 1 or 3 and examined signaling molecules function downstream Results: Forced expression induced marked activation extracellular signal–regulated kinase (ERK) STAT3, but not AKT. Inhibition ERK STAT3 resulted substantial attenuation proliferation expressing either EML4-ALK, suggesting these pathways cancer cells. specific ALK inhibitor TAE684 apoptosis accompanied both upregulation BIM, proapoptotic member Bcl-2 family, downregulation survivin, protein (IAP) EML4-ALK–expressing well H3122 human harboring endogenous Depletion BIM overexpression survivin each inhibited TAE684-induced apoptosis, contribute EML4-ALK–positive Furthermore, found be independently regulated pathways, respectively. Conclusions: inhibitor–induced is mediated resulting from inhibition Clin Cancer Res; 17(8); 2140–8. ©2011 AACR .