by Resistance to cancer therapies remains a major challenge in the treatment of the disease. In order to enhance the effectiveness of cancer treatments, it is crucial to understand the mechanisms behind this resistance. A recent study led by the Protein Kinases and Cancer group of the Vall d’Hebron Research Institute (VHIR), along with the Department of Biochemistry and Molecular Biology and the Institute of Neurosciences of the Universitat Autònoma de Barcelona (UAB), has discovered a new mechanism that can sensitize cancer cells to a specific therapy that has previously been ineffective due to tumor resistance.
The findings of the study, conducted in collaboration with the Biomedical Research in Gynecology group at VHIR, IRB Barcelona, and the Hospital del Mar Research Institute, have been published in the journal Cell Death & Disease.
Over the years, numerous cancer therapies have failed to progress to clinical practice. One such example is TRAIL agonists, which are molecules that bind to cell membrane TRAIL receptors and trigger apoptosis, or programmed cell death. Despite showing promising results in preclinical stages, these drugs have not exhibited the expected efficacy in clinical trials due to tumor cell resistance.
According to Dr. Sergio Espinosa, a researcher from the Protein Kinases and Cancer group at VHIR and UAB, these therapies hold great promise because TRAIL receptors are primarily found in cancer cells, minimizing side effects in healthy cells.
This research has revealed the molecular mechanism responsible for cancer cells’ resistance to the antitumor effects of TRAIL. The study highlights the significant role of the protein kinase ERK5 in this process. Previous studies have shown that ERK5 is involved in cell proliferation and cancer cell survival. The current findings confirm that the activation of this protein also confers resistance to treatments that induce cell death, explains Dr. José Miguel Lizcano, head of the Protein Kinases and Cancer group at VHIR and INc-UAB researcher.
The results of the study demonstrate that inhibiting ERK5 with drugs can restore the sensitivity of cancer cells to antitumor treatments. It is believed that ERK5 inhibitors can enhance the anticancer efficacy of TRAIL agonists, says Dr. Lizcano.
In order to eliminate tumor cells, the immune system plays a crucial role. Natural Killer (NK) cells, a type of immune cell, have potent antitumor effects, partly due to the activation of the TRAIL pathway. The study also suggests that ERK5 inhibitors could enhance the anticancer activity of NK cells.
So far, the analysis has been conducted on cell lines derived from various types of solid tumors, including prostate, lung, cervical, and neuroblastoma cancer. Additionally, 3D cultures and organoids derived from endometrial cancer patients have also been studied. Organoids are excellent laboratory replicas of fragments from a patient’s tumor and retain many key characteristics of the original tumor. In the future, the researchers aim to collaborate with others to conduct clinical trials to test the efficacy of ERK5 inhibitors in cancer patients.
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1. Source: Coherent Market Insights, Public sources, Desk research
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