Research Papers:
Therapeutic efficacy of the bromodomain inhibitor OTX015/MK-8628 in ALK-positive anaplastic large cell lymphoma: an alternative modality to overcome resistant phenotypes
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Abstract
Michela Boi1,2,*, Maria Todaro1,2,*, Valentina Vurchio1, Shao Ning Yang3, John Moon3, Ivo Kwee4,5,6, Andrea Rinaldi4, Heng Pan7,8, Ramona Crescenzo1,2, Mangeng Cheng9, Leandro Cerchietti3, Olivier Elemento7,8, Maria E. Riveiro10, Esteban Cvitkovic10,11, Francesco Bertoni4,12, Giorgio Inghirami1,2,13, The AIRC 5xMille Consortium ‘Genetics-Driven Targeted Management of Lymphoid Malignancies’
1Department of Molecular Biotechnology and Health Science and Center for Experimental Research and Medical Studies (CeRMS), University of Torino, Torino, Italy
2Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA
3Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medical College, New York, NY, USA
4Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona, Switzerland
5Dalle Molle Institute for Artificial Intelligence (IDSIA), Manno, Switzerland
6Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland
7Institute for Computational Biomedicine, Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY, USA
8Institute for Precision Medicine, Weill Cornell Medical College, New York, NY, USA
9In Vitro Pharmacology, Merck Research Laboratory, Boston, MA, USA
10Oncology Therapeutic Development, Clichy, France
11Oncoethix SA (Now Oncoethix GmbH, A Wholly Owned Subsidiary of Merck Sharp & Dohme Corp.), Lucerne, Switzerland
12IOSI Oncology Institute of Southern Switzerland, Bellinzona, Switzerland
13Department of Pathology, and NYU Cancer Center, New York University School of Medicine, New York, NY, USA
*These authors have contributed equally to this work
Correspondence to:
Giorgio Inghirami, email: [email protected]
Francesco Bertoni, email: [email protected]
Keywords: anaplastic large cell lymphoma, BRD inhibitor, OTX015/MK-8628, tyrosine kinase inhibitor, gene expression profiling
Received: July 07, 2016 Accepted: September 19, 2016 Published: October 25, 2016
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.
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