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Therapeutic efficacy of the bromodomain inhibitor OTX015/MK-8628 in ALK-positive anaplastic large cell lymphoma: an alternative modality to overcome resistant phenotypes.

  • Boi M Department of Molecular Biotechnology and Health Science and Center for Experimental Research and Medical Studies (CeRMS), University of Torino, Torino, Italy.
  • Todaro M Department of Molecular Biotechnology and Health Science and Center for Experimental Research and Medical Studies (CeRMS), University of Torino, Torino, Italy.
  • Vurchio V Department of Molecular Biotechnology and Health Science and Center for Experimental Research and Medical Studies (CeRMS), University of Torino, Torino, Italy.
  • Yang SN Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
  • Moon J Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
  • Kwee I Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona, Switzerland.
  • Rinaldi A Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona, Switzerland.
  • Pan H Institute for Computational Biomedicine, Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY, USA.
  • Crescenzo R Department of Molecular Biotechnology and Health Science and Center for Experimental Research and Medical Studies (CeRMS), University of Torino, Torino, Italy.
  • Cheng M In Vitro Pharmacology, Merck Research Laboratory, Boston, MA, USA.
  • Cerchietti L Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
  • Elemento O Institute for Computational Biomedicine, Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY, USA.
  • Riveiro ME Oncology Therapeutic Development, Clichy, France.
  • Cvitkovic E Oncology Therapeutic Development, Clichy, France.
  • Bertoni F Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona, Switzerland.
  • Inghirami G Department of Molecular Biotechnology and Health Science and Center for Experimental Research and Medical Studies (CeRMS), University of Torino, Torino, Italy.
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  • 2016-10-30
Published in:
  • Oncotarget. - 2016
BRD inhibitor
OTX015/MK-8628
anaplastic large cell lymphoma
gene expression profiling
tyrosine kinase inhibitor
Acetanilides
Anaplastic Lymphoma Kinase
Antineoplastic Agents
Antineoplastic Combined Chemotherapy Protocols
Biomarkers, Tumor
Cell Cycle Checkpoints
Cell Line, Tumor
Cell Proliferation
Dose-Response Relationship, Drug
Drug Resistance, Neoplasm
Drug Synergism
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Genetic Predisposition to Disease
Heterocyclic Compounds, 3-Ring
Humans
Inhibitory Concentration 50
Lymphoma, Large-Cell, Anaplastic
Phenotype
Receptor Protein-Tyrosine Kinases
Signal Transduction
Time Factors
Transcriptome
English Anaplastic large cell lymphomas (ALCL) represent a peripheral T-cell lymphoma subgroup, stratified based on the presence or absence of anaplastic lymphoma kinase (ALK) chimeras. Although ALK-positive ALCLs have a more favorable outcome than ALK-negative ALCL, refractory and/or relapsed forms are common and novel treatments are needed. Here we investigated the therapeutic potential of a novel bromodomain inhibitor, OTX015/MK-8628 in ALK-positive ALCLs.The effects of OTX015 on a panel of ALK+ ALCL cell lines was evaluated in terms of proliferation, cell cycle and downstream signaling, including gene expression profiling analyses. Synergy was tested with combination targeted therapies.Bromodomain inhibition with OTX015 led primarily to ALCL cell cycle arrest in a dose-dependent manner, along with downregulation of MYC and its downstream regulated genes. MYC overexpression did not compensate this OTX015-mediated phenotype. Transcriptomic analysis of OTX015-treated ALCL cells identified a gene signature common to various hematologic malignancies treated with bromodomain inhibitors, notably large cell lymphoma. OTX015-modulated genes included transcription factors (E2F2, NFKBIZ, FOS, JUNB, ID1, HOXA5 and HOXC6), members of multiple signaling pathways (ITK, PRKCH, and MKNK2), and histones (clusters 1-3). Combination of OTX015 with the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib led to cell cycle arrest then cell death, and combination with suboptimal doses of the ALK inhibitor CEP28122 caused cell cycle arrest. When OTX015 was associated with GANT61, a selective GLI1/2 inhibitor, C1156Y-resistant ALK ALCL growth was impaired.These findings support OTX015 clinical trials in refractory ALCL in combination with inhibitors of interleukin-2-inducible kinase or SHH/GLI1.
Language
  • English
Open access status
gold
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Persistent URL
https://sonar.ch/global/documents/139422
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