title: Aurora A Kinase Inhibition Selectively Synergizes with Histone Deacetylase Inhibitor through Cytokinesis Failure in T-cell Lymphoma.
abstract: OBJECTIVE
  Aurora A kinase (AAK) is expressed exclusively during mitosis, and plays a critical role in centrosome duplication and spindle formation. Alisertib is a highly selective AAK inhibitor that has demonstrated marked clinical activity of alisertib across a spectrum of lymphomas, though particularly in patients with T-cell lymphoma (TCL). We sought to compare and contrast the activity of alisertib in preclinical models of B-cell lymphoma (BCL) and TCL, and identify combinations worthy of clinical study. High-throughput screening of pralatrexate, the proteasome inhibitor (ixazomib), and the histone deacetylase (HDAC) inhibitor (romidepsin) revealed that only romidepsin synergized with alisertib, and only in models of TCL. We discovered that the mechanism of synergy between AAK inhibitors and HDAC inhibitors appears to be mediated through cytokinesis failure.
  
  
  METHODS
  A high-throughput screening approach was used to identify drugs that were potentially synergistic in combination with alisertib. Live-cell imaging was used to explore the mechanistic basis for the drug: drug interaction between alisertib and romidepsin. An in vivo xenograft TCL model was used to confirm in vitro results.
  
  
  RESULTS
  In vitro, alisertib exhibited concentration-dependent cytotoxicity in BCL and TCL cell lines. Alisertib was synergistic with romidepsin in a T-cell-specific fashion that was confirmed in vivo. Live-cell imaging demonstrated that the combination treatment resulted in profound cytokinesis failure.
  
  
  CONCLUSIONS
  These data strongly suggest that the combination of alisertib and romidepsin is highly synergistic in TCL through modulation of cytokinesis and merits clinical development.
authors: Department of Medicine, Center for Lymphoid Malignancies, Columbia University Medical Center, New York, New York.
authors: Kelly M
authors: KM
authors: Zullo
authors: Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York.
authors: Yige
authors: Y
authors: Guo
authors: University of Tennessee Health Science Center, West Cancer Center, Memphis, Tennessee.
authors: Laurence
authors: L
authors: Cooke
authors: Department of Medicine, Center for Lymphoid Malignancies, Columbia University Medical Center, New York, New York.
authors: Xavier
authors: X
authors: Jirau-Serrano
authors: Department of Medicine, Center for Lymphoid Malignancies, Columbia University Medical Center, New York, New York.
authors: Michael
authors: M
authors: Mangone
authors: Department of Medicine, Center for Lymphoid Malignancies, Columbia University Medical Center, New York, New York.
authors: Luigi
authors: L
authors: Scotto
authors: Department of Medicine, Center for Lymphoid Malignancies, Columbia University Medical Center, New York, New York.
authors: Jennifer E
authors: JE
authors: Amengual
authors: Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York.
authors: Yinghui
authors: Y
authors: Mao
authors: Irving Institute for Clinical and Translational Research, Columbia University Medical Center, New York, New York.
authors: Renu
authors: R
authors: Nandakumar
authors: Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York. Irving Institute for Clinical and Translational Research, Columbia University Medical Center, New York, New York.
authors: Serge
authors: S
authors: Cremers
authors: Mailman School of Public Health, Columbia University, New York, New York.
authors: Jimmy
authors: J
authors: Duong
authors: University of Tennessee Health Science Center, West Cancer Center, Memphis, Tennessee.
authors: Daruka
authors: D
authors: Mahadevan
authors: Department of Medicine, Center for Lymphoid Malignancies, Columbia University Medical Center, New York, New York. owenoconnor@columbia.edu.
authors: Owen A
authors: OA
authors: O'Connor
mesh_terms: D000630:Aminopterin / Q000008:administration & dosage / Q000031:analogs & derivatives; D000818:Animals; D064096:Aurora Kinase A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001381:Azepines / Q000008:administration & dosage / Q000627:therapeutic use; D001896:Boron Compounds / Q000008:administration & dosage; D002453:Cell Cycle; D045744:Cell Line, Tumor; D018385:Centrosome / Q000648:ultrastructure; D048749:Cytokinesis; D047630:Depsipeptides / Q000008:administration & dosage; D004357:Drug Synergism; D005998:Glycine / Q000008:administration & dosage / Q000031:analogs & derivatives; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry*; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D053208:Kaplan-Meier Estimate; D016399:Lymphoma, T-Cell / Q000188:drug therapy / Q000276:immunology*; D051379:Mice; D016513:Mice, SCID; D008938:Mitosis; D009368:Neoplasm Transplantation; D047428:Protein Kinase Inhibitors / Q000737:chemistry*; D011743:Pyrimidines / Q000008:administration & dosage / Q000627:therapeutic use; D008941:Spindle Apparatus; D023041:Xenograft Model Antitumor Assays
chemical_list: C418863:10-propargyl-10-deazaaminopterin; D001381:Azepines; D001896:Boron Compounds; D047630:Depsipeptides; D056572:Histone Deacetylase Inhibitors; C550258:MLN 8237; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C548400:ixazomib; C087123:romidepsin; D064096:Aurora Kinase A; D006655:Histone Deacetylases; D000630:Aminopterin; D005998:Glycine