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

John K. Simmons, Jyoti Patel, Aleksandra Michalowski, Shuling Zhang, Bih Rong Wei, Patrick Sullivan, Ben Gamache, Kenneth Felsenstein, W. Michael Kuehl, R. Mark Simpson, Adriana Zingone, Ola Landgren, Beverly A. Mock*

*Corresponding author for this work

Research output: Contribution to journalArticle

17 Scopus citations

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 invitro, as well as in freshly isolated primary MM patient samples tested exvivo. 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.

Original languageEnglish (US)
Pages (from-to)261-272
Number of pages12
JournalMolecular oncology
Volume8
Issue number2
DOIs
StatePublished - Mar 2014

Keywords

  • Burkitt's lymphoma
  • Entinostat
  • Mantle cell lymphoma
  • Myeloma
  • Plasmacytoma
  • Siroliumus

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Oncology
  • Cancer Research

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    Simmons, J. K., Patel, J., Michalowski, A., Zhang, S., Wei, B. R., Sullivan, P., Gamache, B., Felsenstein, K., Kuehl, W. M., Simpson, R. M., Zingone, A., Landgren, O., & Mock, B. A. (2014). TORC1 and class I HDAC inhibitors synergize to suppress mature B cell neoplasms. Molecular oncology, 8(2), 261-272. https://doi.org/10.1016/j.molonc.2013.11.007