Abstract
BackgroundMammalian target of rapamycin (mTOR) inhibitors have anti-tumor effects against renal cell carcinoma, pancreatic neuroendocrine cancer and breast cancer. In this study, we analyzed the antitumor effects of mTOR inhibitors in small cell lung cancer (SCLC) cells and sought to clarify the mechanism of resistance to mTOR inhibitors.MethodsWe analyzed the antitumor effects of three mTOR inhibitors including everolimus in 7 SCLC cell lines by MTS assay. Gene-chip analysis, receptor tyrosine kinases (RTK) array and Western blotting analysis were performed to identify molecules associated with resistance to everolimus.ResultsOnly SBC5 cells showed sensitivity to everolimus by MTS assay. We established two everolimus resistant-SBC5 cell lines (SBC5 R1 and SBC5 R10) by continuous exposure to increasing concentrations of everolimus stepwise. SPP1 and MYC were overexpressed in both SBC5 R1 and SBC5 R10 by gene-chip analysis. High expression levels of eukaryotic translation initiation factor 4E (eIF4E) were observed in 5 everolimus-resistant SCLC cells and SBC5 R10 cells by Western blotting. MYC siRNA reduced eIF4E phosphorylation in SBC5 cells, suggesting that MYC directly activates eIF4E by an mTOR-independent bypass pathway. Importantly, after reduction of MYC or eIF4E by siRNAs, the SBC5 parent and two SBC5-resistant cells displayed increased sensitivity to everolimus relative to the siRNA controls.ConclusionThese findings suggest that eIF4E has been shown to be an important factor in the resistance to everolimus in SCLC cells. Furthermore, a link between MYC and mTOR-independent eIF4E contribute to the resistance to everolimus in SCLC cells. Control of the MYC-eIF4E axis may be a novel therapeutic strategy for everolimus action in SCLC.
Highlights
Mammalian target of rapamycin inhibitors have anti-tumor effects against renal cell carcinoma, pancreatic neuroendocrine cancer and breast cancer
Effects of Mammalian target of rapamycin (mTOR) Inhibitors on Small Cell Lung Cancer Cells and protein expressionn of AKT/mTOR pathway molecules We examined the anti-tumor activities of three mTOR inhibitors including everolimus, temsirolimus and rapamycin against 7 small cell lung cancer (SCLC) cell lines by MTS assay (Figure 1A)
R10 cells treated with MYC or eukaryotic translation initiation factor 4E (eIF4E) siRNAs reversed resistance to everolimus relative to siRNA controls (Figure 4B, C). These results suggest that MYC and eIF4E collaborate in drug resistance to everolimus, apparently bypassing the inhibitors in an mTOR-independent manner in SCLC cells (Figure 4D)
Summary
Mammalian target of rapamycin (mTOR) inhibitors have anti-tumor effects against renal cell carcinoma, pancreatic neuroendocrine cancer and breast cancer. We analyzed the antitumor effects of mTOR inhibitors in small cell lung cancer (SCLC) cells and sought to clarify the mechanism of resistance to mTOR inhibitors. Small cell lung cancer (SCLC), which is characterized as a neuroendocrine tumor, is one of the most aggressive cancers and is often diagnosed only in late stages. Chemotherapy has a major role in treatment in advanced SCLC patients. Molecularly-targeted therapies have been recently developed for non-small cell lung cancer (NSCLC) treatment. Recent randomized trials using gefitinib, erlotinib, afatinib, and crizotinib have demonstrated significant superiority of these molecularly-targeted drugs on progression-free survival compared with standard chemotherapies as key agents for advanced NSCLC with driver mutations [6,7,8]. Molecularly-targeted agents developed for NSCLC are largely ineffective against SCLC. New targeted drugs are required for therapeutic strategies in SCLC
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