The bromodomain inhibitor OTX015 (MK-8628) exerts anti-tumor activity in triple-negative breast cancer models as single agent and in combination with everolimus

// Ramiro Vazquez 1 , Maria E. Riveiro 2 , Lucile Astorgues-Xerri 2 , Elodie Odore 2, 3 , Keyvan Rezai 3 , Eugenio Erba 1 , Nicolo Panini 1 , Andrea Rinaldi 4 , Ivo Kwee 4, 5, 6 , Luca Beltrame 1 , Mohamed Bekradda 2 , Esteban Cvitkovic 2, 7 , Francesco Bertoni 4, 8 , Roberta Frapolli 1 , Maurizio D'Incalci 1 1 Laboratory of Anti-tumor Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy 2 Oncology Therapeutic Development, Clichy, France 3 Radiopharmacology Department, Curie Institute-Rene Huguenin Hospital, Saint Cloud, France 4 Institute of Oncology Research (IOR), Bellinzona, Switzerland 5 Dalle Molle Institute for Artificial Intelligence (IDSIA), Manno, Switzerland 6 Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland 7 Oncoethix GmbH (formerly Oncoethix SA), Merck Sharp and Dohme Corp., Switzerland 8 Oncology Institute of Southern Switzerland (IOSI), Bellinzona, Switzerland Correspondence to: Ramiro Vazquez, email: ramirobioq@hotmail.com Keywords: OTX015 (MK-8628), bromodomain inhibitor, triple-negative breast cancer, everolimus Received: July 25, 2016      Accepted: November 22, 2016      Published: December 07, 2016 ABSTRACT Triple-negative breast cancer (TNBC) is an aggressive and heterogeneous subgroup of breast tumors clinically defined by the lack of estrogen, progesterone and HER2 receptors, limiting the use of the targeted therapies employed in other breast malignancies. Recent evidence indicates that c-MYC is a key driver of TNBC. The BET-bromodomain inhibitor OTX015 (MK-8628) has potent antiproliferative activity accompanied by c-MYC down-regulation in several tumor types, and has demonstrated synergism with the mTOR inhibitor everolimus in different models. The aim of this study was to evaluate the anti-tumor activity of OTX015 as single agent and in combination with everolimus in TNBC models. OTX015 was assayed in three human TNBC-derived cell lines, HCC1937, MDA-MB-231 and MDA-MB-468, all showing antiproliferative activity after 72 h (GI 50 = 75–650 nM). This was accompanied by cell cycle arrest and decreased expression of cancer stem cells markers. However, c-MYC protein and mRNA levels were only down-regulated in MDA-MB-468 cells. Gene set enrichment analysis showed up-regulation of genes involved in epigenetic control of transcription, chromatin and the cell cycle, and down-regulation of stemness-related genes. In vitro , combination with everolimus was additive in HCC1937 and MDA-MB-231 cells, but antagonistic in MDA-MB-468 cells. In MDA-MB-231 murine xenografts, tumor mass was significantly ( p < 0.05) reduced by OTX015 with respect to vehicle-treated animals (best T/C = 40.7%). Although everolimus alone was not active, the combination was more effective than OTX015 alone (best T/C = 20.7%). This work supports current clinical trials with OTX015 in TNBC (NCT02259114).