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© The Author(s) 2021. ; 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. ; This work was supported by grants from the Instituto de Salud Carlos III (PI15/01180 and PI19/00840, co-funded by European Union ERDF, "A way to make Europe") to A. Esparís-Ogando. A. Sánchez-Fdez was supported by the Cancer Center Network Program from the ISCIII (RD12/0036/0003) and by a predoctoral fellowship from the Scientific Foundation of the Spanish Association Against Cancer (AECC). Our laboratory is supported by grants from the Ministry of Economy and Competitiveness of Spain (BFU2015-71371-R to A. Pandiella), the AECC and the CRIS Cancer Foundation. Our Cancer Research Institute, and the work carried out at our laboratory receive support from the European Community through the regional development funding program (FEDER). We are grateful to Nathanael S. Gray (Dana-Farber Cancer Institute, Boston, Massachusetts) for initially providing us with the compound JWG-071, and Dr. J. Lizcano (UAB, Barcelona, Spain) for advice on its in vivo use.