A new therapeutic strategy to improve treatment of aggressive endometrial cancer

Inhibition of the ERK5 protein kinase reduces the proliferation and survival of endometrial cancer cells, and potentiates standard chemotherapy.

02/11/2022

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 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.

The results support the clinical development of a drug to block ERK5 that would improve the prognosis of endometrial cancer patients.

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