Bronchial carcinoid response to mTOR inhibitors depends on mTOR expression levels

Introduction: Bronchial carcinoids (BCs), originating from endocrine cells dispersed in the respiratory epithelium, can be divided into typical (TBC) and atypical (ABC). TBC are less aggressive, smaller, and much less likely to metastasize, while ABC are more aggressive and metastasize. mTOR has a central role in regulating cell growth, metabolism, and apoptosis. A differential mTOR activation in BCs has been previously demonstrated, suggesting that mTOR pathway might play a predictive role in patients eligible for mTOR-targeted therapies. Aim: To evaluate the effects of mTOR inhibitors on human BCs cells lines. Materials and methods: NCIH720 (ABC) and NCIH727 (TBC) cells were treated with Everolimus or with NVP-BEZ 235, a dual PI3K/mTOR inhibitor. Cell viability, caspase activity and cell cycle progression were evaluated after 72 h. Results: Everolimus inhibits cell viability in both cell lines with a more pronounced effects on NCIH720, does not activate apoptosis but determined G1/G0 accumulation. NVP-BEZ235 had similar effects to Everolimus in terms of cell viability in NCIH727, but was more potent in NCIH720 cells. Caspase activity was not induced by NVP-BEZ 235 in NCIH727, but was enhanced in NCIH720. Western blot and Q-PCR were performed to assess whether this differential effect is due to variations in mTOR expression in BCs cell lines. mTOR expression is 1.5-fold higher in NCIH720 as compared with NCIH727. Conclusion: These data demonstrate that mTOR inhibitors affect BCs cell lines differently depending on mTOR expression.