Insights into the cellular pharmacological properties of the BETinhibitor OTX015/MK-8628 (birabresib), alone and in combination, in leukemia models

VÁZQUEZ, RAMIRO; ASTORGUES-XERRI, LUCILE; ODORE, ELODIE; KAHATT, CARMEN; MACKENZIE, SARAH; BEKRADDA, MOHAMED; COUDÉ, MARIE-MAGDELAINE; DOMBRET, HERVE; GARDIN, CLAUDE; LOKIEC, FRANCOIS; RAYMOND, ERIC; NOEL, KAY; CVITKOVIC, ESTEBAN; HERAIT, PATRICE; BERTONI, FRANCESCO; RIVEIRO, MARÍA EUGENIA

LEUKEMIA AND LYMPHOMA

TAYLOR & FRANCIS LTD

Lugar: Londres; Año: 2019

1042-8194

Background: Although poor clinical outcomes are often, the standard treatment of leukemias has remained largely unchanged for over four decades. BET chromatin readers were recently shown to maintain aberrant chromatin states in several hematologic malignancies. This preclinical study aimed to characterize the cellular pharmacodynamics and pharmacokinetic properties of OTX015 (MK-8628), the first-in-man BET inhibitor, alone and in combination with approved therapies in hematologic malignancies. Methods: A wide range of acute and chronic leukemia models was used to explore OTX015 effect on cell proliferation, cell cycle and apoptosis using MTT assay and FACS analysis, respectively. Several leukemia key genes mRNA and protein expressions levels were analyzed with Western blot and RT-qPCR assays, respectively, and the effect of OTX015 in combination was explored using the Chou-Talalay method. Results: OTX015 displayed antiproliferative effects in leukemia models, along with cell cycle arrest and apoptosis induction. Although the kinetics of MYC and its target genes may be differentially regulated in sensitive and resistant cells -while intracellular OTX015 levels were similar and stable in all the cell lines-, MYC suppression was not related to OTX015 sensitivity. Furthermore, OTX015 presented synergistic and additive effects in combination with cytotoxic and targeted drugs in leukemia models. Conclusion: OTX015 is active as single agent or in combination in a broad range of leukemia types leading to cell cycle arrest and induction of apoptosis at concentrations that are achieved in plasma of patients with hematologic malignancies treated with it.