by Autonomous University of Barcelona

ERK5 inhibition impairs EC cell proliferation. A Genomic profiles of components of the MEK5-ERK5 pathway in EC patients obtained from Uterine Corpus Endometrial Carcinoma data set (TCGA, PanCancer Atlas). Data set from cBiportal. MAPK7, ERK5 gene; MAP2K5, MEK5. B Kaplan–Meier plots overall survival (left) and progression-free (right) in uterine corpus endometrial carcinoma patients with high (red), quartile 1) or normal (blue, quartile 2–3) ERK5 mRNA levels (data set from cBioportal). P values were obtained using log-rank test. C Chemical structure of JWG-071. D Immunoblot analysis of the effect of JWG-071 on EGF stimulation. E MTT cytotoxicity (48 h) assay in a panel of human EC cells. F 14-day clonogenic assay. G Effect of ERK5 silencing on the proliferation of EC cell. ERK5 silencing was carried out with two different specific siRNA sequences. Scr., scramble siRNA. Cell proliferation was measured at three days of culture using crystal violet assays. ^***, P < 0.001. H LRRK2 or DCLK1 inhibition does not affect human EC cell proliferation. Ishikawa or AN3CA cells were incubated for 48 h with either the specific DCLK1 inhibitor DCLK1-IN-1 or the LRRK2 specific inhibitor MLi-2, and cell proliferation was assessed by crystal violet assay. I Effect of ERK5 inhibitors JWG-071 and AX15836 in EGF-induced cell proliferation. Histograms show number of cells at day 4 referred to cells at day 0. ^$, P < 0.05; ^$$$, P < 0.001 EGF vs. vehicle. **, P < 0.01; ***, P < 0.001 ERK5i vs. EGF. J, JWG-071 blocks EGF-induced ERK5 nuclear localization. HeLa cells were pre-incubated with 3 µM JWG-071 prior stimulation with 50 nM EGF (30 min), fractionated into the cytosolic and nuclear fractions, and protein expression analyzed by immunoblot. Hsp90, cytosolic marker; CREB-1, nuclear marker. K ERK5 inhibition impairs EGF-induced c-Jun expression in Ishikawa cells. Immunoblot analysis. L JWG-071 impairs ERK5-mediated AP-1 transcriptional activity. Hela cells transfected with vectors encoding pAP-1–luciferase reporter and pRL-CMV-Renilla were subjected to a dual-luciferase reporter assay. **, P < 0.005. Credit: Cellular and Molecular Life Sciences (2022). DOI: 10.1007/s00018-022-04541-6

Endometrial cancer is the most common type of gynecological cancer and is the fourth most common type of tumor in women in developed countries. Although it has a good prognosis if detected early, advanced and aggressive cases have a high mortality rate and are often resistant to standard chemotherapy treatments. Now, a study published in Cellular and Molecular Life Sciences identified a new therapeutic strategy to tackle endometrial cancer (EC), based on inhibition of the MAPK kinase ERK5.

Pharmacological blockade of ERK5 not only impairs proliferation and survival of EC cells, but also potentiates the anticancer activity of chemotherapy.

The study has been led by researchers from the Protein Kinases in Cancer Research group at the Vall d'Hebron Research Institute (VHIR), the Department of Biochemistry and Molecular Biology of the Universitat Autònoma de Barcelona (UAB) and the UAB Institute of Neurosciences (INc-UAB), in collaboration with the Biomedical Research in Gynecology group of VHIR and the Oncological Pathology research group at Institute of Biomedical Research of Lleida (IRBLleida).

In recent years, the ERK5 protein has shown to play a role in the development of several types of solid cancers.

"We observed that up to 48% of patients with endometrial cancer show alterations in components of the ERK5 signaling pathway, which correlate with lower overall survival and reduced progression-free survival. In this work, we found that ERK5 is a promising therapeutic target for the treatment of advanced endometrial cancer," explains Dr. Nora Diéguez, researcher at the Protein Kinases in Cancer Research group at VHIR and Institute of Neurosciences of UAB.

"Understanding the signaling pathways that are altered in endometrial cancer allows the design of new therapeutic strategies to improve the prognosis of these patients," adds Dr. José Miguel Lizcano, head of the Protein Kinases in Cancer Research group at VHIR, researcher at INc-UAB and professor at the Department of Biochemistry and Molecular Biology of UAB.

In this work, carried out using cellular and mouse models, the researchers used a new ERK5 inhibitor (JWG-071), currently in preclinical development. They observed that inhibition of the ERK5 protein reduces the proliferation of tumor cells, and it impairs the growth of tumors in animal models.

This effect is mediated through NF-κB, a transcription factor that regulates the proliferation and survival of different tumor types, including endometrial cancer. "Since ERK5 inhibition potentiates the efficacy of chemotherapy in animal models, we believe that ERK5 could be an effective target to tackle endometrial cancer," says Dr. Lizcano.

JWG-071 is the first oral and selective ERK5 inhibitor that has shown antitumor activity and safety in animal models. "Our results support the clinical development of JWG-071, to explore the therapeutic potential of ERK5 inhibitors for endometrial cancer patients," concludes Dr. Lizcano.

More information: Nora Diéguez-Martínez et al, The ERK5/NF-κB signaling pathway targets endometrial cancer proliferation and survival, Cellular and Molecular Life Sciences (2022). DOI: 10.1007/s00018-022-04541-6

Journal information: Cellular and Molecular Life Sciences 

Provided by Autonomous University of Barcelona