PurposeEpigenetic regulation is crucial in mammalian development and maintenance of tissue-cell specific functions. Perturbation of epigenetic balance may lead to alterations in gene expression, resulting in cellular transformation and malignancy. Previous studies in Ewing sarcoma (ES) have shown that the Nucleosome Remodeling Deacetylase (NuRD) complex binds directly to EWS-FLI1 oncoprotein and modulates its transcriptional activity. The role of EWS-FLI1 as a driver of proliferation and transformation in ES is widely known, but the effect of epigenetic drugs on fusion activity remains poorly described. The present study evaluated the combination effects of the histone deacetylases inhibitor suberoylanilide hydroxamic acid (SAHA) and Lysine-specific demethylase1 inhibitor (HCI-2509) on different biological functions in ES and in comparison to monotherapy treatments.ResultsThe study of proliferation and cell viability showed a synergistic effect in most ES cell lines analyzed. An enhanced effect was also observed in the induction of apoptosis, together with accumulation of cells in G1 phase and a blockage of the migratory capacity of ES cell lines. Treatment, either in monotherapy or in combination, caused a significant decrease of EWS-FLI1 mRNA and protein levels and this effect is mediated in part by fusion gene promoter regulation. The anti-tumor effect of this combination was confirmed in patient-derived xenograft mouse models, in which only the combination treatment led to a statistically significant decrease in tumor volume.ConclusionsThe combination of SAHA and HCI-2509 is proposed as a novel treatment strategy for ES patients to inhibit the essential driver of this sarcoma and tumor growth.

Despite advances in its treatment, lung cancer still represents the most common and lethal tumor. Because of that, efforts to decipher the pathophysiological actors that may promote lung tumor generation/progression are being made, with the final aim of establishing new therapeutic options. Using a transgenic mouse model, we formerly demonstrated that the sole activation of the MEK5/ERK5 MAPK route had a pathophysiological role in the onset of lung adenocarcinomas. Given the prevalence of that disease and its frequent dismal prognosis, our findings opened the possibility of targeting the MEK5/ERK5 route with therapeutic purposes. Here we have explored such possibility. We found that increased levels of MEK5/ERK5 correlated with poor patient prognosis in lung cancer. Moreover, using genetic as well as pharmacological tools, we show that targeting the MEK5/ERK5 route is therapeutically effective in lung cancer. Not only genetic disruption of ERK5 by CRISPR/Cas9 caused a relevant inhibition of tumor growth in vitro and in vivo; such ERK5 deficit augmented the antitumoral effect of agents normally used in the lung cancer clinic. The clinical correlation studies together with the pharmacological and genetic results establish the basis for considering the targeting of the MEK5/ERK5 route in the therapy for lung cancer.