Clinical, genetic and pharmacological data support targeting the MEK5/ERK5 module in lung cancer

Abstract

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.

Clinical Significance and Regulation of ERK5 Expression and Function in Cancer

“…By gene expression profiling, ERK5 mRNA is overexpressed in primary brain tumors, particularly in glioblastomas (GBM) [ 138 ], and in TNBC, a subgroup among primary BCs [ 139 ]. Although variable among samples, the ERK5 mRNA level is higher in LC tissue samples than in normal lung tissue [ 39 , 140 ]. In a small cohort of osteosarcoma patients, ERK5 overexpression has been found in most cases.…”

“…ERK5 amplification has also been reported in Skin Cutaneous Melanoma (SKCM) in the TCGA database [ 87 ] and detected in 4% of the NSCLC by FISH analysis [ 89 ]. Finally, copy number gain or amplification of ERK5, corresponding to higher mRNA expression of the ERK5 gene, has been reported in 18.9% and 13.5% of lung adenocarcinomas (LUAD) and lung squamous carcinomas (LUSC), respectively [ 39 ].…”

“…In the osteosarcoma patients treated with chemotherapy, the ERK5 overexpression was associated with the presence of metastasis, low Huvos grade, poor treatment response, and worse OS [ 143 ]. In LC patients, high levels of ERK5 mRNA expression are associated with a worse prognosis, and this relationship is stronger among the LUAD cohort [ 39 , 140 ]. Specifically, the analysis of pooled data from the LUAD cohorts, through the KM-Plotter tool, found a reduced disease-free survival (DFS) with high ERK5 expression [ 140 ].…”

“…The overexpression of MEKK2/3 has been observed in different tumors such as colorectal, prostate, esophageal, breast, cervical, kidney, and lung cancer (LC) [ 35 , 36 , 37 , 38 ]; the latter one is also characterized by an increased MEK5/ERK5 signaling axis phosphorylation, and it has been recently demonstrated that pharmacological and genetic inhibition of both proteins, reduces LC cell proliferation [ 39 ].…”

“…In addition, Tusa et al [ 80 ] also observed that the Hedgehog (HH)-GLI signaling axis can enhance the transcription and the activation of ERK5, and that shRNA-mediated suppression of ERK5, reversed the HH-GLI-dependent proliferation of melanoma cells. In LC, characterized by an increased MEK5/ERK5 signaling axis phosphorylation, was recently demonstrated that pharmacological and genetic inhibition of both proteins reduced LC cell proliferation [ 39 ]. Shukla et al [ 81 ] reported a link between asbestos-related ERK5 upregulation and proliferation of mesothelioma cells, as well as the inhibition of proliferative-related genes after ERK5 blockade.…”