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BET bromodomain inhibitor birabresib in mantle cell lymphoma: in vivo activity and identification of novel combinations to overcome adaptive resistance
  1. Chiara Tarantelli1,
  2. Elena Bernasconi1,
  3. Eugenio Gaudio1,
  4. Luciano Cascione1,2,
  5. Valentina Restelli3,
  6. Alberto Jesus Arribas1,
  7. Filippo Spriano1,
  8. Andrea Rinaldi1,
  9. Afua Adjeiwaa Mensah1,
  10. Ivo Kwee1,2,4,
  11. Maurilio Ponzoni5,
  12. Emanuele Zucca6,
  13. Laura Carrassa3,
  14. Maria E Riveiro7,
  15. Keyvan Rezai8,
  16. Anastasios Stathis6,
  17. Esteban Cvitkovic7,9,
  18. Francesco Bertoni1
  1. 1 Università della Svizzera italiana (USI), Institute of Oncology Research (IOR), Bellinzona, Switzerland
  2. 2 Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland
  3. 3 IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy
  4. 4 Dalle Molle Institute for Artificial Intelligence (IDSIA), Manno, Switzerland
  5. 5 Department of Onco-Haematology, Unit of Lymphoid Malignancies, San Raffaele Scientific Institute, Milan, Italy
  6. 6 IOSI Oncology Institute of Southern Switzerland, Bellinzona, Switzerland
  7. 7 OTD Oncology, Therapeutic Development, Clichy, France
  8. 8 Institut Curie, Hôpital René Huguenin, Saint-Cloud, France
  9. 9 OncoEthix GmbH, a wholly owned subsidiary of Merck Sharp & Dohme Corp, and Merck & Co., Inc, Kenilworth, New Jersey, USA
  1. Correspondence to Dr Francesco Bertoni; frbertoni{at}mac.com

Abstract

Background The outcome of patients affected by mantle cell lymphoma (MCL) has improved in recent years, but there is still a need for novel treatment strategies for these patients. Human cancers, including MCL, present recurrent alterations in genes that encode transcription machinery proteins and of proteins involved in regulating chromatin structure, providing the rationale to pharmacologically target epigenetic proteins. The Bromodomain and Extra Terminal domain (BET) family proteins act as transcriptional regulators of key signalling pathways including those sustaining cell viability. Birabresib (MK-8628/OTX015) has shown antitumour activity in different preclinical models and has been the first BET inhibitor to successfully undergo early clinical trials.

Materials and methods The activity of birabresib as a single agent and in combination, as well as its mechanism of action was studied in MCL cell lines.

Results Birabresib showed in vitro and in vivo activities, which appeared mediated via downregulation of MYC targets, cell cycle and NFKB pathway genes and were independent of direct downregulation of CCND1. Additionally, the combination of birabresib with other targeted agents (especially pomalidomide, or inhibitors of BTK, mTOR and ATR) was beneficial in MCL cell lines.

Conclusion Our data provide the rationale to evaluate birabresib in patients affected by MCL.

  • lymphoma
  • BET bromodomain
  • epigenetics
  • MYC

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Footnotes

  • CT and EB contributed equally.

  • Contributors CT cowrote the manuscript, designed and performed experiments, interpreted data; EB designed and performed experiments, interpreted data; EG wrote the manuscript, designed experiments and interpreted data; VR, AA, FS, AAM and MP performed experiments; AR performed gene expression profiling; IK and LuC performed data mining; EZ, EC and AS provided advice; LaC and MER provided advice and designed experiments; KR performed experiments; FB designed the study, interpreted data and cowrote the manuscript. CT and EB equally contributed. All authors have approved the final manuscript.

  • Funding This work was partially supported with institutional research funds from Oncoethix SA, the Nelia et Amadeo Barletta Foundation and the Gelu Foundation (to FB); KLS-3636-02-2015 (to AR) and Mu.Ta.Lig. COST Action CA15135 (to EG), Italian Association for Cancer Research (AIRC) (to L.Ca.).

  • Competing interests Francesco Bertoni and Anastasios Stathis have received institutional research funds from Oncology Therapeutic Development. Maria E. Riveiro was an employee of Oncology Therapeutic Development. EC is a Founder, Chief Scientific Officer, shareholder of Oncoethix SA, holder of birabresib license. EZ has received research funds from Celgene, Novartis, Mundipharma, Roche, Pharmacyclics Inc., Johnson & Johnson’s Janssen Pharmaceutical, Gilead. The remaining Authors have no conflict of interest.

  • Patient consent Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement Profiling data are available at the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) (http://www.ncbi.nlm.nih.gov/geo) database (GSE110134).

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