Differential Effects of PI3K and Dual PI3K/mTOR Inhibition in Rat Prolactin-Secreting Pituitary Tumors

Mol Cancer Ther. 2016 Jun;15(6):1261-70. doi: 10.1158/1535-7163.MCT-15-0891. Epub 2016 Mar 16.

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.

MeSH terms

  • Aminopyridines / administration & dosage*
  • Aminopyridines / pharmacology
  • Animals
  • Cell Cycle Proteins / metabolism
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Humans
  • Imidazoles / administration & dosage*
  • Imidazoles / pharmacology
  • Morpholines / administration & dosage*
  • Morpholines / pharmacology
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphorylation / drug effects
  • Pituitary Neoplasms / drug therapy*
  • Pituitary Neoplasms / metabolism
  • Prolactin / metabolism*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Quinolines / administration & dosage*
  • Quinolines / pharmacology
  • Rats
  • Signal Transduction / drug effects*
  • TOR Serine-Threonine Kinases / metabolism
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

Substances

  • Aminopyridines
  • Cell Cycle Proteins
  • Imidazoles
  • Morpholines
  • NVP-BKM120
  • Quinolines
  • Prolactin
  • Phosphatidylinositol 3-Kinases
  • TOR Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • dactolisib