title: The bromodomain inhibitor OTX015 (MK-8628) exerts anti-tumor activity in triple-negative breast cancer models as single agent and in combination with everolimus.
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 (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).
authors.affiliation: Laboratory of Anti-tumor Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
authors.forename: Ramiro
authors.initials: R
authors.lastname: Vázquez
authors.affiliation: Oncology Therapeutic Development, Clichy, France.
authors.forename: María E
authors.initials: ME
authors.lastname: Riveiro
authors.affiliation: Oncology Therapeutic Development, Clichy, France.
authors.forename: Lucile
authors.initials: L
authors.lastname: Astorgues-Xerri
authors.affiliation: Oncology Therapeutic Development, Clichy, France.|Radiopharmacology Department, Curie Institute-René Huguenin Hospital, Saint Cloud, France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Odore
authors.affiliation: Radiopharmacology Department, Curie Institute-René Huguenin Hospital, Saint Cloud, France.
authors.forename: Keyvan
authors.initials: K
authors.lastname: Rezai
authors.affiliation: Laboratory of Anti-tumor Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
authors.forename: Eugenio
authors.initials: E
authors.lastname: Erba
authors.affiliation: Laboratory of Anti-tumor Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
authors.forename: Nicolò
authors.initials: N
authors.lastname: Panini
authors.affiliation: Institute of Oncology Research (IOR), Bellinzona, Switzerland.
authors.forename: Andrea
authors.initials: A
authors.lastname: Rinaldi
authors.affiliation: Institute of Oncology Research (IOR), Bellinzona, Switzerland.|Dalle Molle Institute for Artificial Intelligence (IDSIA), Manno, Switzerland.|Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland.
authors.forename: Ivo
authors.initials: I
authors.lastname: Kwee
authors.affiliation: Laboratory of Anti-tumor Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Beltrame
authors.affiliation: Oncology Therapeutic Development, Clichy, France.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Bekradda
authors.affiliation: Oncology Therapeutic Development, Clichy, France.|Oncoethix GmbH (formerly Oncoethix SA), Merck Sharp and Dohme Corp., Switzerland.
authors.forename: Esteban
authors.initials: E
authors.lastname: Cvitkovic
authors.affiliation: Institute of Oncology Research (IOR), Bellinzona, Switzerland.|Oncology Institute of Southern Switzerland (IOSI), Bellinzona, Switzerland.
authors.forename: Francesco
authors.initials: F
authors.lastname: Bertoni
authors.affiliation: Laboratory of Anti-tumor Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Frapolli
authors.affiliation: Laboratory of Anti-tumor Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: D'Incalci
mesh_terms: D000083:Acetanilides / Q000494:pharmacology*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D000068338:Everolimus / Q000494:pharmacology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology*; D006801:Humans; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D013997:Time Factors; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000083:Acetanilides; D018797:Cell Cycle Proteins; D006575:Heterocyclic Compounds, 3-Ring; C489427:MYC protein, human; C000605331:OTX015; D016271:Proto-Oncogene Proteins c-myc; D000068338:Everolimus; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
keywords: OTX015 (MK-8628); bromodomain inhibitor; everolimus; triple-negative breast cancer