Research Papers:

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 Vázquez _, María E. Riveiro, Lucile Astorgues-Xerri, Elodie Odore, Keyvan Rezai, Eugenio Erba, Nicolò Panini, Andrea Rinaldi, Ivo Kwee, Luca Beltrame, Mohamed Bekradda, Esteban Cvitkovic, Francesco Bertoni, Roberta Frapolli and Maurizio D'Incalci

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Oncotarget. 2017; 8:7598-7613. https://doi.org/10.18632/oncotarget.13814

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Ramiro Vázquez1, María E. Riveiro2, Lucile Astorgues-Xerri2, Elodie Odore2,3, Keyvan Rezai3, Eugenio Erba1, Nicolò Panini1, Andrea Rinaldi4, Ivo Kwee4,5,6, Luca Beltrame1, Mohamed Bekradda2, Esteban Cvitkovic2,7, Francesco Bertoni4,8, Roberta Frapolli1, Maurizio D'Incalci1

1Laboratory of Anti-tumor Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy

2Oncology Therapeutic Development, Clichy, France

3Radiopharmacology Department, Curie Institute-René Huguenin Hospital, Saint Cloud, France

4Institute of Oncology Research (IOR), Bellinzona, Switzerland

5Dalle Molle Institute for Artificial Intelligence (IDSIA), Manno, Switzerland

6Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland

7Oncoethix GmbH (formerly Oncoethix SA), Merck Sharp and Dohme Corp., Switzerland

8Oncology Institute of Southern Switzerland (IOSI), Bellinzona, Switzerland

Correspondence to:

Ramiro Vázquez, email: [email protected]

Keywords: OTX015 (MK-8628), bromodomain inhibitor, triple-negative breast cancer, everolimus

Received: July 25, 2016     Accepted: November 22, 2016     Published: December 07, 2016


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 (GI50 = 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).

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