Abstract
BackgroundTriple negative breast cancer (TNBC) is an incurable disease where novel therapeutic strategies are needed. Proteolysis targeting chimeric (PROTAC) are novel compounds that promote protein degradation by binding to an ubiquitin ligase. In this work, we explored the antitumoral activity of two novel BET-PROTACs, MZ1 and ARV-825, in TNBC, ovarian cancer and in a BET inhibitor resistant model.MethodsOVCAR3, SKOV3, BT549, MDA-MB-231 cell lines and the JQ1 resistant cell line MDA-MB-231R were evaluated. MTTs, colony-forming assay, three-dimensional cultures in matrigel, flow cytometry, and western blots were performed to explore the anti-proliferative effect and biochemical mechanism of action of MZ1 and ARV-825. In vivo studies included BALB/c nu/nu mice engrafted with MDA-MB-231R cells.ResultsThe BET-PROTACs MZ1 and ARV-825 efficiently downregulated the protein expression levels of the BET protein BRD4, in MDA-MB-231 and MDA-MB-231R. MZ1 and ARV-825 also showed an antiproliferative effect on sensitive and resistant cells. This effect was corroborated in other triple negative (BT549) and ovarian cancer (SKOV3, OVCAR3) cell lines. MZ1 provoked G2/M arrest in MDA-MB-231. In addition, a profound effect on caspase-dependent apoptosis was observed in both sensitive and resistant cells. No synergistic activity was observed when it was combined with docetaxel, cisplatin or olaparib. Finally, in vivo administration of MZ1 rescued tumor growth in a JQ1-resistant xenograft model, reducing the expression levels of BRD4.ConclusionsUsing both in vitro and in vivo approaches, we describe the profound activity of BET-PROTACs in parental and BETi-resistant TNBC models. This data provides options for further clinical development of these agents in TNBC.
Highlights
Triple negative breast cancer (TNBC) is an incurable disease where novel therapeutic strategies are needed
A reduction of the bromo and extra terminal domain proteins (BET) proteins levels was observed after ARV-825 treatment, a Proteolysis targeting chimeric (PROTAC) that uses OTX-015, another BET inhibitors (BETi), as a backbone [15]
In vitro efficacy of BET-PROTACS in naïve and resistant cells we explored the antiproliferative effect of the BETPROTAC inhibitors MZ1 and ARV-825 when compared with their counterparts JQ1 and OTX015, in MDA-MB
Summary
Triple negative breast cancer (TNBC) is an incurable disease where novel therapeutic strategies are needed. Several mechanisms have been described to be implicated in the resistance to this family of compounds, including the presence of a stem cell phenotype, the activation of polo-like kinase 1 (PLK1), or the basal activity of intracellular signaling kinases like protein kinase B (AKT) or Cyclin-Dependent Kinase Activating Kinase (CSK1) [7,8,9,10,11,12]. Reverting this resistance is crucial for BETi-based therapies to succeed
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