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

Abstract

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