Marinov M Ziogas A Pardo OE Tan LT Dhillon T Mauri FA Lane HA Lemoine NR Zangemeister-Wittke U Seckl MJ Arcaro A 2009 PURPOSE The Akt/mammalian target of rapamycin (mTOR) pathway is frequently activated in human cancers and plays an important role in small cell lung cancer (SCLC) biology. We investigated the potential of targeting mTOR signaling as a novel antitumor approach in SCLC. EXPERIMENTAL DESIGN The expression of mTOR in patient specimens and in a panel of SCLC cell lines was analyzed. The effects on SCLC cell survival and downstream signaling were determined following mTOR inhibition by the rapamycin derivative RAD001 (Everolimus) or down-regulation by small interfering RNA. RESULTS We found elevated expression of mTOR in patient specimens and SCLC cell lines, compared with normal lung tissue and normal lung epithelial cells. RAD001 treatment impaired basal and growth factor-stimulated cell growth in a panel of SCLC cell lines. Cells with increased Akt pathway activation were more sensitive to RAD001. Accordingly, a constitutive activation of the Akt/mTOR pathway was sufficient to sensitize resistant SCLC cells to the cytotoxic effect of RAD001. In the sensitive cells, RAD001 showed a strong additive effect to the proapoptotic action of the chemotherapeutic agent etoposide. Intriguingly, we observed low Bcl-2 family proteins levels in the SCLC cells with a constitutive Akt pathway activation, whereas an increased expression was detected in the RAD001-resistant SCLC cells. An antisense construct targeting Bcl-2 or a Bcl-2-specific inhibitor was able to sensitize resistant SCLC cells to RAD001. Moreover, SCLC tumor growth in vivo was significantly inhibited by RAD001. CONCLUSION Together, our data show that inhibiting mTOR signaling with RAD001 potently disrupts growth and survival signaling in human SCLC cells. application/pdf https://sonar.ch/global/documents/4326 eng info:eu-repo/semantics/altIdentifier/doi/10.1158/1078-0432.CCR-08-2166 info:eu-repo/semantics/altIdentifier/pmid/19228731 info:eu-repo/semantics/openAccess Clinical cancer research : an official journal of the American Association for Cancer Research. - 2009 Animals Antineoplastic Agents Carcinoma, Small Cell Cell Line, Tumor Cyclin-Dependent Kinase Inhibitor p21 Drug Resistance, Neoplasm Etoposide Everolimus Humans Lung Neoplasms Mice Protein Kinases Proto-Oncogene Proteins c-akt Proto-Oncogene Proteins c-bcl-2 Signal Transduction Sirolimus Stem Cell Factor TOR Serine-Threonine Kinases AKT/mTOR pathway activation and BCL-2 family proteins modulate the sensitivity of human small cell lung cancer cells to RAD001. http://purl.org/coar/resource_type/c_6501