Endocrine Abstracts

NVP-BEZ235 is an orally available ATP competitive inhibitor of class I PI3K and mTOR. As such it suppresses Akt phosphorylation downstreams to PI3K and to mTOR complex 2 in addition to p70/S6K1 phosphorylation downstreams to mTOR complex 1 and displays potent antiproliferative activity in tumors with dysregulated the PI3K/Akt pathway. Administration of NVP-BEZ235 in human nonfunctioning pituitary tumors in primary cell culture suppressed cell viability by more than 50% in 37 out of 40 cases. The effect was cytostatic causing cell cycle arrest at the G1 phase. Transition through the G1 phase is governed by cyclin-cyclin dependent kinase (Cdk) complexes which phosphorylate retinoblastoma, triggering E2F transcription and the expression of proteins that are needed to drive the cell further into mitosis. NVP-BEZ235 treatment in immortalized pituitary tumor cells suppressed E2F transcriptional activity and subsequently cyclin E levels. NVP-BEZ235 decreased cyclin D1 and D3 levels, but only at high concentrations (100 nM) and did not affect Cdk4/6 levels. In contract it increased the cell cycle inhibitor p27/Kip1 levels (even at lower concentrations; 10 nM), but not its transcription indicating regulation at posttranscriptional level. Altogether these data indicate a potential for the dual PI3K/mTOR inhibitor NVP-BEZ235 for the pharmacological treatment of non-functioning pituitary adenomas.