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

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 man...

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Autores principales: Cuenca-López, María Dolores, Serrano-Heras, Gemma, Montero, Juan Carlos, Corrales-Sánchez, Verónica, Gomez-Juarez, Mónica, Gascón-Escribano, Maria José, Carlos Morales, Jorge, Voisin, Veronique, Núñez, Luz Elena, Morís, Francisco, Bader, Gary D., Pandiella, Atanasio, Ocaña, Alberto
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4695035/
https://www.ncbi.nlm.nih.gov/pubmed/26314846
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author Cuenca-López, María Dolores
Serrano-Heras, Gemma
Montero, Juan Carlos
Corrales-Sánchez, Verónica
Gomez-Juarez, Mónica
Gascón-Escribano, Maria José
Carlos Morales, Jorge
Voisin, Veronique
Núñez, Luz Elena
Morís, Francisco
Bader, Gary D.
Pandiella, Atanasio
Ocaña, Alberto
author_facet Cuenca-López, María Dolores
Serrano-Heras, Gemma
Montero, Juan Carlos
Corrales-Sánchez, Verónica
Gomez-Juarez, Mónica
Gascón-Escribano, Maria José
Carlos Morales, Jorge
Voisin, Veronique
Núñez, Luz Elena
Morís, Francisco
Bader, Gary D.
Pandiella, Atanasio
Ocaña, Alberto
author_sort Cuenca-López, María Dolores
collection PubMed
description 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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spelling pubmed-46950352016-01-20 Antitumor activity of the novel multi-kinase inhibitor EC-70124 in triple negative breast cancer Cuenca-López, María Dolores Serrano-Heras, Gemma Montero, Juan Carlos Corrales-Sánchez, Verónica Gomez-Juarez, Mónica Gascón-Escribano, Maria José Carlos Morales, Jorge Voisin, Veronique Núñez, Luz Elena Morís, Francisco Bader, Gary D. Pandiella, Atanasio Ocaña, Alberto Oncotarget Research Paper 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. Impact Journals LLC 2015-08-12 /pmc/articles/PMC4695035/ /pubmed/26314846 Text en Copyright: © 2015 Cuenca-López et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Cuenca-López, María Dolores
Serrano-Heras, Gemma
Montero, Juan Carlos
Corrales-Sánchez, Verónica
Gomez-Juarez, Mónica
Gascón-Escribano, Maria José
Carlos Morales, Jorge
Voisin, Veronique
Núñez, Luz Elena
Morís, Francisco
Bader, Gary D.
Pandiella, Atanasio
Ocaña, Alberto
Antitumor activity of the novel multi-kinase inhibitor EC-70124 in triple negative breast cancer
title Antitumor activity of the novel multi-kinase inhibitor EC-70124 in triple negative breast cancer
title_full Antitumor activity of the novel multi-kinase inhibitor EC-70124 in triple negative breast cancer
title_fullStr Antitumor activity of the novel multi-kinase inhibitor EC-70124 in triple negative breast cancer
title_full_unstemmed Antitumor activity of the novel multi-kinase inhibitor EC-70124 in triple negative breast cancer
title_short Antitumor activity of the novel multi-kinase inhibitor EC-70124 in triple negative breast cancer
title_sort antitumor activity of the novel multi-kinase inhibitor ec-70124 in triple negative breast cancer
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4695035/
https://www.ncbi.nlm.nih.gov/pubmed/26314846
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