Antitumor activity of the novel multi-kinase inhibitor EC-70124 in triple negative breast cancer
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María Dolores Cuenca-López1,*, Gemma Serrano-Heras1,*, Juan Carlos Montero2, Verónica Corrales-Sánchez1, Mónica Gomez-Juarez1, Maria José Gascón-Escribano1, Jorge Carlos Morales1, Veronique Voisin3, Luz Elena Núñez4, Francisco Morís4, Gary D. Bader3, Atanasio Pandiella2, Alberto Ocaña1
1Translational Research Unit, Albacete University Hospital, Albacete, Spain
2Cancer Research Center, CSIC-University of Salamanca, Spain
3The Donnelly Centre, University of Toronto, Canada
4EntreChem SL, Oviedo, Spain
*These authors have contributed equally to this work
Alberto Ocaña, e-mail: [email protected]
Keywords: EC-70124, triple negative, breast cancer, kinase inhibitor
Received: March 20, 2015 Accepted: July 31, 2015 Published: August 12, 2015
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.
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