title: Mechanisms of activity of the TORC1 inhibitor everolimus in Waldenstrom macroglobulinemia.
abstract: OBJECTIVE
  The TORC1 inhibitor everolimus has previously shown significant activity as a single agent in hematologic malignancies, with reported responses of 30% to 70% in Waldenstrom macroglobulinemia. However, the specific mechanisms by which this class of mTOR inhibitors exerts anti-Waldenstrom macroglobulinemia activity have not been fully investigated. We therefore sought to dissect the mechanisms of everolimus-dependent modulation of Waldenstrom macroglobulinemia cell survival.
  
  
  METHODS
  We confirmed that everolimus targets mTOR in patients treated with everolimus and responding to therapy. We evaluated the effect of everolimus on proliferation and survival of primary Waldenstrom macroglobulinemia cells, as well as of other IgM-secreting lymphoma cell lines. Everolimus-dependent mechanisms of induced apoptosis and its effect on Waldenstrom macroglobulinemia cells in the context of bone marrow microenvironment have been also evaluated. miRNA-155 loss-of-function studies were conducted. Moreover, the combinatory effect of bortezomib and rituximab has been tested.
  
  
  RESULTS
  We showed that everolimus targeted mTOR downstream signaling pathways, ex vivo, in patients responding to everolimus treatment. Everolimus induced toxicity in primary Waldenstrom macroglobulinemia cells, as well as in other IgM-secreting lymphoma cells, supported by cell-cycle arrest and caspase-dependent and -independent induction of apoptosis. Importantly, everolimus targeted Waldenstrom macroglobulinemia cells even in the context of bone marrow milieu, where it affected migration, adhesion, and angiogenesis. Everolimus-dependent anti-Waldenstrom macroglobulinemia activity was partially driven by miRNA-155. Moreover, everolimus synergized with bortezomib and rituximab in targeting Waldenstrom macroglobulinemia cells, as shown by synergistic inhibition of p65/ and p50/NF-κB activities.
  
  
  CONCLUSIONS
  These findings provide a better understanding of the mechanisms that are responsible for everolimus-induced anti-Waldenstrom macroglobulinemia activity.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Aldo M
authors.initials: AM
authors.lastname: Roccaro
authors.forename: Antonio
authors.initials: A
authors.lastname: Sacco
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Jia
authors.forename: Ranjit
authors.initials: R
authors.lastname: Banwait
authors.forename: Patricia
authors.initials: P
authors.lastname: Maiso
authors.forename: Feda
authors.initials: F
authors.lastname: Azab
authors.forename: Ludmila
authors.initials: L
authors.lastname: Flores
authors.forename: Salomon
authors.initials: S
authors.lastname: Manier
authors.forename: Abdel Kareem
authors.initials: AK
authors.lastname: Azab
authors.forename: Irene M
authors.initials: IM
authors.lastname: Ghobrial
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D058846:Antibodies, Monoclonal, Murine-Derived / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001853:Bone Marrow / Q000473:pathology; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D017322:Clinical Trials, Phase II as Topic; D004357:Drug Synergism; D000068338:Everolimus; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D035683:MicroRNAs / Q000502:physiology; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors*; D011719:Pyrazines / Q000494:pharmacology; D000069283:Rituximab; D015398:Signal Transduction; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured / Q000187:drug effects; D059016:Tumor Microenvironment; D008258:Waldenstrom Macroglobulinemia / Q000188:drug therapy* / Q000473:pathology
chemical_list: D020533:Angiogenesis Inhibitors; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D001897:Boronic Acids; C524942:MIRN155 microRNA, human; D035683:MicroRNAs; D046912:Multiprotein Complexes; D011719:Pyrazines; D000069283:Rituximab; D000069286:Bortezomib; D000068338:Everolimus; C546842:MTOR protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus