title: TORC1 and class I HDAC inhibitors synergize to suppress mature B cell neoplasms.
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.
authors.affiliation: Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, USA.
authors.forename: John K
authors.initials: JK
authors.lastname: Simmons
authors.affiliation: Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, USA.
authors.forename: Jyoti
authors.initials: J
authors.lastname: Patel
authors.affiliation: Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, USA.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Michalowski
authors.affiliation: Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, USA.
authors.forename: Shuling
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, USA.
authors.forename: Bih-Rong
authors.initials: BR
authors.lastname: Wei
authors.affiliation: Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Sullivan
authors.affiliation: Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, USA.
authors.forename: Ben
authors.initials: B
authors.lastname: Gamache
authors.affiliation: Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, USA.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Felsenstein
authors.affiliation: Genetics Branch, National Cancer Institute, National Institutes of Health, USA.
authors.forename: W Michael
authors.initials: WM
authors.lastname: Kuehl
authors.affiliation: Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, USA.
authors.forename: R Mark
authors.initials: RM
authors.lastname: Simpson
authors.affiliation: Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, USA.
authors.forename: Adriana
authors.initials: A
authors.lastname: Zingone
authors.affiliation: Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, USA.
authors.forename: Ola
authors.initials: O
authors.lastname: Landgren
authors.affiliation: Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, USA. Electronic address: mockb@mail.nih.gov.
authors.forename: Beverly A
authors.initials: BA
authors.lastname: Mock
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D045744:Cell Line, Tumor; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D016393:Lymphoma, B-Cell / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008819:Mice, Nude; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D010954:Plasmacytoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011725:Pyridines / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D001549:Benzamides; D056572:Histone Deacetylase Inhibitors; D046912:Multiprotein Complexes; D011725:Pyridines; C118739:entinostat; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases
keywords: Burkitt's lymphoma; Entinostat; Mantle cell lymphoma; Myeloma; Plasmacytoma; Siroliumus