title: Differential Effects of PI3K and Dual PI3K/mTOR Inhibition in Rat Prolactin-Secreting Pituitary Tumors.
abstract: Aggressive pituitary tumors are rare but difficult to manage, as there is no effective chemotherapy to restrict their growth and cause their shrinkage. Within these tumors, growth-promoting cascades, like the PI3K/mTOR pathway, appear to be activated. We tested the efficacy of two inhibitors of this pathway, NVP-BKM120 (Buparlisib; pan-PI3K) and NVP-BEZ235 (dual PI3K/mTOR), both in vitro on immortalized pituitary tumor cells (GH3) and on primary cell cultures of human pituitary tumors and in vivo on a rat model of prolactin (PRL) tumors (SMtTW3). In vitro, NVP-BEZ235 had a potent apoptotic and cytostatic effect that was characterized by decreased cyclin D/E and Cdk4/2 protein levels and subsequent accumulation of cells in G1 In vivo, the effect was transient, with a decrease in mitotic index and increase in apoptosis; long-term treatment had no significant inhibitory effect on tumor growth. In contrast, while NVP-BKM120 had little effect in vitro, it dramatically limited tumor growth in vivo Increased Akt phosphorylation observed only in the NVP-BEZ235-treated tumors may explain the differential response to the two inhibitors. Primary cell cultures of human PRL pituitary tumors responded to NVP-BEZ235 with reduced cell viability and decreased hormone secretion, whereas NVP-BKM120 had little effect. Altogether, these results show a potential for PI3K inhibitors in the management of aggressive pituitary tumors. Mol Cancer Ther; 15(6); 1261-70. ©2016 AACR.
authors.affiliation: INSERM U1052, CNRS UMR5286, Cancer Research Center of Lyon, Lyon, France. Université Lyon 1, Lyon, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Chanal
authors.affiliation: INSERM U1052, CNRS UMR5286, Cancer Research Center of Lyon, Lyon, France. Université Lyon 1, Lyon, France.
authors.forename: Pascale
authors.initials: P
authors.lastname: Chevallier
authors.affiliation: Centre de Biologie Est, Groupement Hospitalier Est, Hospices Civils de Lyon, Bron, France. gerald.raverot@chu-lyon.fr.
authors.forename: Véronique
authors.initials: V
authors.lastname: Raverot
authors.affiliation: INSERM U1052, CNRS UMR5286, Cancer Research Center of Lyon, Lyon, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Fonteneau
authors.affiliation: Max-Planck Institute for Psychiatry, Munich, Germany.
authors.forename: Kristin
authors.initials: K
authors.lastname: Lucia
authors.affiliation: Max-Planck Institute for Psychiatry, Munich, Germany.
authors.forename: Jose Luis
authors.initials: JL
authors.lastname: Monteserin Garcia
authors.affiliation: INSERM U1052, CNRS UMR5286, Cancer Research Center of Lyon, Lyon, France.
authors.forename: Alexa
authors.initials: A
authors.lastname: Rachwan
authors.affiliation: INSERM U1052, CNRS UMR5286, Cancer Research Center of Lyon, Lyon, France. Université Lyon 1, Lyon, France. Service de Neurochirurgie, Groupement Hospitalier Est, Hospices Civils de Lyon, Bron, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Jouanneau
authors.affiliation: Université Lyon 1, Lyon, France. Centre de Pathologie Est, Groupement Hospitalier Est, Hospices Civils de Lyon, Bron, France. INSERM U1028, CNRS UMR5292, Lyon Neuroscience Research Center, Neuro-oncology and Neuro-inflammation Team, Lyon, France.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Trouillas
authors.affiliation: Université Lyon 1, Lyon, France. INSERM U1028, CNRS UMR5292, Lyon Neuroscience Research Center, Neuro-oncology and Neuro-inflammation Team, Lyon, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Honnorat
authors.affiliation: INSERM U1052, CNRS UMR5286, Cancer Research Center of Lyon, Lyon, France. Université Lyon 1, Lyon, France.
authors.forename: Carole
authors.initials: C
authors.lastname: Auger
authors.affiliation: Max-Planck Institute for Psychiatry, Munich, Germany.
authors.forename: Marily
authors.initials: M
authors.lastname: Theodoropoulou
authors.affiliation: INSERM U1052, CNRS UMR5286, Cancer Research Center of Lyon, Lyon, France. Université Lyon 1, Lyon, France. Fédération d'Endocrinologie, Groupement Hospitalier Est, Hospices Civils de Lyon, Bron, France.
authors.forename: Gérald
authors.initials: G
authors.lastname: Raverot
mesh_terms: D000631:Aminopyridines / Q000008:administration & dosage* / Q000494:pharmacology; D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage* / Q000494:pharmacology; D009025:Morpholines / Q000008:administration & dosage* / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010911:Pituitary Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011388:Prolactin / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011804:Quinolines / Q000008:administration & dosage* / Q000494:pharmacology; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000631:Aminopyridines; D018797:Cell Cycle Proteins; D007093:Imidazoles; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D011388:Prolactin; D051057:Proto-Oncogene Proteins c-akt; D011804:Quinolines; D058570:TOR Serine-Threonine Kinases; C571178:NVP-BKM120; C531198:dactolisib