TORC1 and class I HDAC inhibitors synergize to suppress mature B cell neoplasms

Mol Oncol. 2014 Mar;8(2):261-72. doi: 10.1016/j.molonc.2013.11.007. Epub 2013 Dec 3.

Abstract

Enhanced proliferative signaling and loss of cell cycle regulation are essential for cancer progression. Increased mitogenic signaling through activation of the mTOR pathway, coupled with deregulation of the Cyclin D/retinoblastoma (Rb) pathway is a common feature of lymphoid malignancies, including plasmacytoma (PCT), multiple myeloma (MM), Burkitt's lymphoma (BL), and mantle cell lymphoma (MCL). Here we evaluate the synergy of pharmacologically affecting both of these critical pathways using the mTOR inhibitor sirolimus and the histone deacetylase inhibitor entinostat. A dose-matrix screening approach found this combination to be highly active and synergistic in a panel of genetically diverse human MM cell lines. Synergy and activity was observed in mouse PCT and human BL and MCL cell lines tested in vitro, as well as in freshly isolated primary MM patient samples tested ex vivo. This combination had minimal effects on healthy donor cells and retained activity when tested in a co-culture system simulating the protective interaction of cancer cells with the tumor microenvironment. Combining sirolimus with entinostat enhanced cell cycle arrest and apoptosis. At the molecular level, entinostat increased the expression of cell cycle negative regulators including CDKN1A (p21) and CDKN2A (p16), while the combination decreased critical growth and survival effectors including Cyclin D, BCL-XL, BIRC5, and activated MAPK.

Keywords: Burkitt's lymphoma; Entinostat; Mantle cell lymphoma; Myeloma; Plasmacytoma; Siroliumus.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Benzamides / pharmacology*
  • Cell Line, Tumor
  • Histone Deacetylase Inhibitors / pharmacology*
  • Humans
  • Lymphoma, B-Cell / drug therapy*
  • Lymphoma, B-Cell / genetics
  • Lymphoma, B-Cell / metabolism
  • Lymphoma, B-Cell / mortality
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Mice, Nude
  • Multiple Myeloma / drug therapy*
  • Multiple Myeloma / genetics
  • Multiple Myeloma / metabolism
  • Multiple Myeloma / pathology
  • Multiprotein Complexes / antagonists & inhibitors*
  • Multiprotein Complexes / genetics
  • Multiprotein Complexes / metabolism
  • Plasmacytoma / drug therapy*
  • Plasmacytoma / genetics
  • Plasmacytoma / metabolism
  • Plasmacytoma / pathology
  • Pyridines / pharmacology*
  • TOR Serine-Threonine Kinases / antagonists & inhibitors*
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism

Substances

  • Benzamides
  • Histone Deacetylase Inhibitors
  • Multiprotein Complexes
  • Pyridines
  • entinostat
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1