title: Antitumor activity of the novel multi-kinase inhibitor EC-70124 in triple negative breast cancer.
abstract: Disseminated triple negative breast cancer (TNBC) is an incurable disease with limited therapeutic options beyond chemotherapy. Therefore, identification of druggable vulnerabilities is an important aim. Protein kinases play a central role in cancer and particularly in TNBC. They are involved in many oncogenic functions including migration, proliferation, genetic stability or maintenance of stem-cell like properties. In this article we describe a novel multi-kinase inhibitor with antitumor activity in this cancer subtype. EC-70124 is a hybrid indolocarbazole analog obtained by combinatorial biosynthesis of Rebeccamycin and Staurosporine genes that showed antiproliferative effect and in vivo antitumoral activity. Biochemical experiments demonstrated the inhibition of the PI3K/mTOR and JAK/STAT pathways. EC-70124 mediated DNA damage leading to cell cycle arrest at the G2/M phase. Pathway analyses identified several deregulated functions including cell proliferation, migration, DNA damage, regulation of stem cell differentiation and reversion of the epithelial-mesenchymal transition (EMT) phenotype, among others. Combination studies showed a synergistic interaction of EC-70124 with docetaxel, and an enhanced activity in vivo. Furthermore, EC-70124 had a good pharmacokinetic profile. In conclusion these experiments demonstrate the antitumor activity of EC-70124 in TNBC paving the way for the future clinical development of this drug alone or in combination with chemotherapy.
authors: Translational Research Unit, Albacete University Hospital, Albacete, Spain.
authors: María Dolores
authors: MD
authors: Cuenca-López
authors: Translational Research Unit, Albacete University Hospital, Albacete, Spain.
authors: Gemma
authors: G
authors: Serrano-Heras
authors: Cancer Research Center, CSIC-University of Salamanca, Salamanca, Spain.
authors: Juan Carlos
authors: JC
authors: Montero
authors: Translational Research Unit, Albacete University Hospital, Albacete, Spain.
authors: Verónica
authors: V
authors: Corrales-Sánchez
authors: Translational Research Unit, Albacete University Hospital, Albacete, Spain.
authors: Mónica
authors: M
authors: Gomez-Juarez
authors: Translational Research Unit, Albacete University Hospital, Albacete, Spain.
authors: Maria José
authors: MJ
authors: Gascón-Escribano
authors: Translational Research Unit, Albacete University Hospital, Albacete, Spain.
authors: Jorge Carlos
authors: JC
authors: Morales
authors: The Donnelly Centre, University of Toronto, Toronto, Canada.
authors: Veronique
authors: V
authors: Voisin
authors: EntreChem SL, Oviedo, Spain.
authors: Luz Elena
authors: LE
authors: Núñez
authors: EntreChem SL, Oviedo, Spain.
authors: Francisco
authors: F
authors: Morís
authors: The Donnelly Centre, University of Toronto, Toronto, Canada.
authors: Gary D
authors: GD
authors: Bader
authors: Cancer Research Center, CSIC-University of Salamanca, Salamanca, Spain.
authors: Atanasio
authors: A
authors: Pandiella
authors: Translational Research Unit, Albacete University Hospital, Albacete, Spain.
authors: Alberto
authors: A
authors: Ocaña
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D020411:Oligonucleotide Array Sequence Analysis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D064726:Triple Negative Breast Neoplasms / Q000473:pathology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors
keywords: EC-70124; breast cancer; kinase inhibitor; triple negative