The BET bromodomain inhibitor OTX015 affects pathogenetic pathways in preclinical B-cell tumor models and synergizes with targeted drugs

Michela Boi, Eugenio Gaudio, Paola Bonetti, Ivo Kwee, Elena Bernasconi, Chiara Tarantelli, Andrea Rinaldi, Monica Testoni, Luciano Cascione, Maurilio Ponzoni, Afua Adjeiwaa Mensah, Anastasios Stathis, Georg Stussi, María Eugenia Riveiro, Patrice Herait, Giorgio Inghirami, Esteban Cvitkovic, Emanuele Zucca, Francesco Bertoni

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose: In cancer cells, the epigenome is often deregulated, and inhibition of the bromodomain and extra-terminal (BET) family of bromodomain-containing proteins is a novel epigenetic therapeutic approach. Preliminary results of an ongoing phase I trial have reported promising activity and tolerability with the new BET bromodomain inhibitor OTX015. Experimental Design: We assessed the preclinical activity of OTX015 as single agent and in combination in mature B-cell lymphoma models and performed in vitro and in vivo experiments to identify the mechanism of action and the genetic features associated with sensitivity to the compound. Results: OTX015 showed antiproliferative activity in a large panel of cell lines derived from mature B-cell lymphoid tumors with median IC50 of 240 nmol/L, without signi ficant differences among the different histotypes. In vitro and in vivo experiments showed that OTX015 targeted NFKB/TLR/JAK/STAT signaling pathways, MYC- and E2F1-regulated genes, cell-cycle regulation, and chromatin structure. OTX015 presented in vitro synergism with several anticancer agents, especially with mTOR and BTK inhibitors. Gene expression signatures associated with different degrees of sensitivity to OTX015 were identified. Although OTX015 was mostly cytostatic, the compound induced apoptosis in a genetically defined subgroup of cells, derived from activated B-cell-like diffuse large B-cell lymphoma, bearing wtTP53, mutations in MYD88, and CD79B or CARD11. Conclusions: Together with the data coming from the ongoing phase I study, the in vitro and in vivo data presented here provide the basis for further clinical investigation of OTX015 as single agent and in combination therapies.

Original languageEnglish
Pages (from-to)1628-1638
Number of pages11
JournalClinical Cancer Research
Volume21
Issue number7
DOIs
Publication statusPublished - Apr 1 2015

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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