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.
Highlights
Basal-like breast tumors and its clinical correlate the triple negative breast cancer (TNBC) are both an unmet disease, where no therapeutic strategies exist beyond treatment with classical chemotherapy [1]
Due to its high proliferation this tumor subtype is more sensitive to agents that act on functions related to cell division such as chemotherapies or novel anti-mitotic agents [9,10,11,12]
We explored the interaction of both agents in MDA-MB231 and HS578T, observing that increasing doses of the Bromodomain and extraterminal domain (BET) inhibitor JQ1 augmented the effect of Volasertib given at its IC50 dose (Figure 2A)
Summary
Basal-like breast tumors and its clinical correlate the triple negative breast cancer (TNBC) are both an unmet disease, where no therapeutic strategies exist beyond treatment with classical chemotherapy [1]. Due to its heterogeneity the identification of relevant druggable targets has been unsuccessful and no novel compounds have reached yet the clinical setting [2, 3] In this context, the discovery of relevant non-oncogenic vulnerabilities that could be therapeutically exploited is a main goal. Due to its high proliferation this tumor subtype is more sensitive to agents that act on functions related to cell division such as chemotherapies or novel anti-mitotic agents [9,10,11,12] In this context, it has been suggested that agents against kinases that participate in the mitotic process could have a relevant place in the future clinical armamentarium [13]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
