title: Therapeutic efficacy of the bromodomain inhibitor OTX015/MK-8628 in ALK-positive anaplastic large cell lymphoma: an alternative modality to overcome resistant phenotypes.
abstract: 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.
authors: Department of Molecular Biotechnology and Health Science and Center for Experimental Research and Medical Studies (CeRMS), University of Torino, Torino, Italy.|Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA.
authors: Michela
authors: M
authors: Boi
authors: Department of Molecular Biotechnology and Health Science and Center for Experimental Research and Medical Studies (CeRMS), University of Torino, Torino, Italy.|Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA.
authors: Maria
authors: M
authors: Todaro
authors: Department of Molecular Biotechnology and Health Science and Center for Experimental Research and Medical Studies (CeRMS), University of Torino, Torino, Italy.
authors: Valentina
authors: V
authors: Vurchio
authors: Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
authors: Shao Ning
authors: SN
authors: Yang
authors: Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
authors: John
authors: J
authors: Moon
authors: Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona, Switzerland.|Dalle Molle Institute for Artificial Intelligence (IDSIA), Manno, Switzerland.|Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland.
authors: Ivo
authors: I
authors: Kwee
authors: Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona, Switzerland.
authors: Andrea
authors: A
authors: Rinaldi
authors: Institute for Computational Biomedicine, Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY, USA.|Institute for Precision Medicine, Weill Cornell Medical College, New York, NY, USA.
authors: Heng
authors: H
authors: Pan
authors: Department of Molecular Biotechnology and Health Science and Center for Experimental Research and Medical Studies (CeRMS), University of Torino, Torino, Italy.|Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA.
authors: Ramona
authors: R
authors: Crescenzo
authors: In Vitro Pharmacology, Merck Research Laboratory, Boston, MA, USA.
authors: Mangeng
authors: M
authors: Cheng
authors: Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
authors: Leandro
authors: L
authors: Cerchietti
authors: Institute for Computational Biomedicine, Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY, USA.|Institute for Precision Medicine, Weill Cornell Medical College, New York, NY, USA.
authors: Olivier
authors: O
authors: Elemento
authors: Oncology Therapeutic Development, Clichy, France.
authors: Maria E
authors: ME
authors: Riveiro
authors: Oncology Therapeutic Development, Clichy, France.|Oncoethix SA (Now Oncoethix GmbH, A Wholly Owned Subsidiary of Merck Sharp & Dohme Corp.), Lucerne, Switzerland.
authors: Esteban
authors: E
authors: Cvitkovic
authors: Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona, Switzerland.|IOSI Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.
authors: Francesco
authors: F
authors: Bertoni
authors: Department of Molecular Biotechnology and Health Science and Center for Experimental Research and Medical Studies (CeRMS), University of Torino, Torino, Italy.|Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA.|Department of Pathology, and NYU Cancer Center, New York University School of Medicine, New York, NY, USA.
authors: Giorgio
authors: G
authors: Inghirami
mesh_terms: D000083:Acetanilides / Q000494:pharmacology*; D000077548:Anaplastic Lymphoma Kinase; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000235:genetics*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D017728:Lymphoma, Large-Cell, Anaplastic / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D010641:Phenotype; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D059467:Transcriptome
chemical_list: D000083:Acetanilides; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D006575:Heterocyclic Compounds, 3-Ring; C000605331:OTX015; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases
keywords: BRD inhibitor; OTX015/MK-8628; anaplastic large cell lymphoma; gene expression profiling; tyrosine kinase inhibitor