mTOR pathway expression predicts sensitivity to mTOR and PI3K/mTOR inhibitors in human bronchial carcinoids

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: MON 292-305-MEN1, MEN2 & Pheochromocytomas
Basic/Clinical
Monday, June 17, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board MON-305
Maria Chiara Zatelli*1, Teresa Gagliano1, Mariaenrica Bellio1, Erica Gentilin1, Daniela Molè1, Federico Tagliati2, Marco Schiavon3, Narciso Giorgio Cavallesco1, Fiorella Calabrese3, Maria Rosaria Ambrosio4, Federico Rea3 and Ettore Ciro degli Uberti1
1University of Ferrara, Ferrara, Italy, 2University of Ferrara, FERRARA, Italy, 3University of Padova, Padova, Italy, 4Endocrinology, University of Ferrara, Ferrara, Italy
Background: Bronchial carcinoids (BCs) 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.

Aim: 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.

Results: 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. We also show that, in addition to total mTOR levels, putative markers of BC sensitivity to mTOR inhibitors are represented by higher AKT, p70S6K and ERK1/2 protein levels. Finally, we validated these markers in an independent BC group.

Conclusion: 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 a 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

Nothing to Disclose: MCZ, TG, MB, EG, DM, FT, MS, NGC, FC, MRA, FR, ECD

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

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