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Antitumor activity of the novel multi-kinase inhibitor EC-70124 in triple negative breast cancer

2015; Impact Journals LLC; Volume: 6; Issue: 29 Linguagem: Inglês

10.18632/oncotarget.4736

1949-2553

María D. Cuenca-López, Gemma Serrano‐Heras, Juan Carlos Montero, Verónica Corrales‐Sánchez, Mónica Gómez-Juárez Sango, Maria José Gascón-Escribano, Jorge Carlos Morales, Véronique Voisin, Luz Elena Núñez, Francisco Morís, Gary D. Bader, Atanasio Pandiella, Alberto Ocaña,

Cancer therapeutics and mechanisms

// María Dolores Cuenca-López 1, * , Gemma Serrano-Heras 1, * , Juan Carlos Montero 2 , Verónica Corrales-Sánchez 1 , Mónica Gomez-Juarez 1 , Maria José Gascón-Escribano 1 , Jorge Carlos Morales 1 , Veronique Voisin 3 , Luz Elena Núñez 4 , Francisco Morís 4 , Gary D. Bader 3 , Atanasio Pandiella 2 , Alberto Ocaña 1 1 Translational Research Unit, Albacete University Hospital, Albacete, Spain 2 Cancer Research Center, CSIC-University of Salamanca, Spain 3 The Donnelly Centre, University of Toronto, Canada 4 EntreChem SL, Oviedo, Spain * These authors have contributed equally to this work Correspondence to: Alberto Ocaña, e-mail: albertoo@sescam.jccm.es Keywords: EC-70124, triple negative, breast cancer, kinase inhibitor Received: March 20, 2015 Accepted: July 31, 2015 Published: August 12, 2015 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.