mTOR, p70S6K, AKT and ERK1/2 levels predict sensitivity to mTOR and PI3K/mTOR inhibitors in human bronchial carcinoids

Bronchial carcinoids (BC) are rare neuroendocrine tumors that are still orphan of medical treatment. Human BC primary cultures may display resistance to Everolimus, an inhibitor of the mammalian target of rapamycin (mTOR), in terms of cell viability reduction. Our aim is to assess whether the novel dual PI3K/mTOR inhibitor, NVP-BEZ235, may be effective in Everolimus-resistant human BC tissues and cell lines. In addition, we search for possible markers of mTOR inhibitors efficacy, that may help in identifying the patients that may benefit from mTOR inhibitors treatment, sparing them from ineffective therapy. We found that NVP-BEZ235 is twice as potent as Everolimus in reducing cell viability and activating apoptosis in human BC tissues that display sensitivity to mTOR inhibitors, but is not effective in Everolimus-resistant BC tissues and cell lines, that by-pass cyclin D1 down-regulation and escape G0/G1 blockade. Rebound AKT activation was not observed in response to treatment with either mTOR inhibitor in 'resistant' BC cells. In addition to total mTOR levels, putative markers of BC sensitivity to mTOR inhibitors are represented by AKT, p70S6K and ERK1/2 protein levels. Finally, we validated these markers in an independent BC group. These data indicate that the dual PI3K/mTOR inhibitor NVP-BEZ235 is more potent than Everolimus in reducing human BC cell proliferation. 'Resistant' cells display lower levels of mTOR, p70S6K, AKT and ERK1/2, indicating that these proteins may be useful as predictive markers of resistance to mTOR and PI3K/mTOR inhibitors in human BC