Novel therapeutic strategies are needed for the treatment of triple negative breast cancer (TNBC). Inhibition of bromo and extraterminal domains (BET) has shown an anti-proliferative effect in TNBC as well as a synergistic interaction with polo-like kinase (PLK) inhibitors. As for many other therapeutic interventions, resistance to BET inhibitors is expected to occur at a given treatment point.
We generated two resistant models to the BET inhibitor JQ1, MDA-MB 231R and HS578TR. Western-blot, flow cytometry analysis, genomic and pharmacologic inhibition were executed to evaluate the anti-proliferative activity and biochemical effect. Nude mice were used to explore the in vivo pharmacological efficacy.
We report the generation of two resistant models to the BET inhibitor JQ1. In both models, resistant cells were particularly sensitive to PLK1 inhibition, and reduced cell proliferation in 2D and 3D cell cultures. Although PLK1 levels were similar in sensitive and resistant cell lines, pharmacological inhibition of BRD4 using JQ1 reduced PLK1 to a less extent in the resistant model, effect not observed with BRD4 gene downregulation. PLK1 inhibitor volasertib induced G2/M arrest in both cell lines, and this effect was more evident in resistant cells, in addition to an increase in pH3 and pCDK1. Combination of volasertib and JQ1 induced apoptosis that was partially caspase dependent. A slight activation of Erk1/2 and pS6 was observed in the resistant model, but the inhibition of these kinases did not have a different effect on proliferation compared with the sensitive one. Finally, JQ1-resistant cells xenografted in mice displayed resistance to JQ1 that was reversed after administration of the PLK1 inhibitor volasertib.
PLK1 inhibition reverts resistance to BET inhibitors in our in vivo and in vitro models. These findings open avenues for further drug combinations in the clinical setting.
Universidad de Castilla-La Mancha.
Instituto de Salud Carlos III; ACEPAIN; CRIS CANCER; Diputación Albacete; UCLM.
All authors have declared no conflicts of interest.