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

• Published in: Oncotarget 2015-09, Vol.6 (29), p.27923-27937
• Main Authors: Cuenca-López, María Dolores, Serrano-Heras, Gemma, Montero, Juan Carlos, Corrales-Sánchez, Verónica, Gomez-Juarez, Mónica, Gascón-Escribano, Maria José, Morales, Jorge Carlos, Voisin, Veronique, Núñez, Luz Elena, Morís, Francisco, Bader, Gary D, Pandiella, Atanasio, Ocaña, Alberto
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Blotting, Western; Cell Line, Tumor; Cell Movement - drug effects; Cell Proliferation - drug effects; Epithelial-Mesenchymal Transition - drug effects; Female; Humans; Immunohistochemistry; Mice; Mice, Inbred BALB C; Oligonucleotide Array Sequence Analysis; Protein Kinase Inhibitors - pharmacology; Research Paper; Reverse Transcriptase Polymerase Chain Reaction; Triple Negative Breast Neoplasms - pathology; Xenograft Model Antitumor Assays
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.4736

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.