BET inhibitor OTX015 targets BRD2 and BRD4 and decreases c-MYC in acute leukemia cells

// Marie-Magdelaine Coudé 1,2,* , Thorsten Braun 1,3,* , Jeannig Berrou 1 , Mélanie Dupont 1 , Sibyl Bertrand 1 , Aline Masse 1 , Emmanuel Raffoux 1,4 , Raphaël Itzykson 1,4 , Marc Delord 5 , Maria E. Riveiro 6 , Patrice Herait 7 , André Baruchel 1,8 , Hervé Dombret 1,4 and Claude Gardin 1,3 1 Laboratoire de Transfert des Leucémies, Institut Universitaire d’Hématologie, University Paris VII, Paris, France 2 Laboratory of Hematology, Hôpital Saint-Louis (Assistance Publique - Hôpitaux de Paris and University Paris VII), Paris, France 3 Hematology Department, Hôpital Avicenne (Assistance Publique - Hôpitaux de Paris and University Paris XIII), Bobigny, France 4 Leukemia Unit, Hematology Department, Hôpital Saint-Louis (Assistance Publique - Hôpitaux de Paris and University Paris VII), Paris, France 5 Bioinformatics, Institut Universitaire d’Hématologie, University Paris VII, Paris, France 6 Oncology Therapeutic Development, Clichy, France 7 Oncoethix, Lausanne, Switzerland 8 Department of Pediatric Hemato-Immunology, Hôpital Robert Debré (Assistance Publique - Hôpitaux de Paris and University Paris VII), Paris, France * These authors have contributed equally to this work Correspondence to: Claude Gardin, email: // Keywords : OTX015, BET inhibitors, c-MYC, HEXIM1, acute leukemias Received : November 26, 2014 Accepted : April 08, 2015 Published : May 14, 2015 Abstract The bromodomain (BRD) and extraterminal (BET) proteins including BRD2, BRD3 and BRD4 have been identified as key targets for leukemia maintenance. A novel oral inhibitor of BRD2/3/4, the thienotriazolodiazepine compound OTX015, suitable for human use, is available. Here we report its biological effects in AML and ALL cell lines and leukemic samples. Exposure to OTX015 lead to cell growth inhibition, cell cycle arrest and apoptosis at submicromolar concentrations in acute leukemia cell lines and patient-derived leukemic cells, as described with the canonical JQ1 BET inhibitor. Treatment with JQ1 and OTX15 induces similar gene expression profiles in sensitive cell lines, including a c-MYC decrease and an HEXIM1 increase. OTX015 exposure also induced a strong decrease of BRD2, BRD4 and c-MYC and increase of HEXIM1 proteins, while BRD3 expression was unchanged. c-MYC , BRD2, BRD3, BRD4 and HEXIM1 mRNA levels did not correlate however with viability following exposure to OTX015. Sequential combinations of OTX015 with other epigenetic modifying drugs, panobinostat and azacitidine have a synergic effect on growth of the KASUMI cell line. Our results indicate that OTX015 and JQ1 have similar biological effects in leukemic cells, supporting OTX015 evaluation in a Phase Ib trial in relapsed/refractory leukemia patients.