Targeting basal-like breast tumors with bromodomain and extraterminal domain (BET) and polo-like kinase inhibitors

// Cristina Nieto-Jimenez 1 , Ana Alcaraz-Sanabria 1 , Javier Perez-Pena 1 , Veronica Corrales-Sanchez 1 , Gemma Serrano-Heras 1 , Eva M. Galan-Moya 3 , Leticia Serrano-Oviedo 1 , Juan Carlos Montero 2 , Miguel Burgos 3 , Juan Llopis 3 , Atanasio Pandiella 2 , Alberto Ocana 3 1 Translational Research Unit, Albacete University Hospital, Albacete, Spain 2 Cancer Research Center, CSIC-University of Salamanca, Salamanca, Spain 3 Centro Regional de Investigaciones Biomedicas (CRIB), Universidad de Castilla La Mancha, Albacete, Spain Correspondence to: Alberto Ocana, email: albertoo@sescam.jccm.es Keywords: breast cancer, triple negative breast cancer, polo-like kinases, BET inhibitors, JQ1 Received: June 20, 2016     Accepted: November 07, 2016     Published: January 3, 2017 ABSTRACT Metastatic triple negative breast cancer (TNBC) is an incurable disease with limited therapeutic options, and no targeted therapies available. Triple negative tumors and the basal-like genomic subtype, are both characterized by a high proliferation rate and an increase in cell division. In this context, protein kinases involved in the mitotic formation have a relevant role in this tumor subtype. Recently, Bromodomain and extraterminal domain (BET) inhibitors have shown to be active in this disease by modulating the expression of several transcription factors. In this article, by using an “in silico” approach, we identified genomic functions that can be inhibited pharmacologically in basal-like tumors. Functional annotation analyses identified “cell division” and “regulation of transcription” as upregulated functions. When focus on cell division, we identified the polo-like kinase 1 (PLK) as an upregulated kinase. The PLK inhibitor Volasertib had the strongest anti-proliferative effect compared with other inhibitors against mitotic kinases. Gene expression analyses demonstrated that the BET inhibitor JQ1 reduced the expression of kinases involved in cell division, and synergized with Volasertib in a panel of triple negative cell lines. Combination of both agents augmented cell death. Similarly, combination of both compounds reduced the expression of stem cell markers. Globally, this data demonstrates the synergistic interaction between BET and PLK inhibitors, paving the way for their future clinical development.