Recently, treatment with MEK inhibitors has been shown to be an effective treatment option for metastatic melanoma. Treatment efficacy is dependent on inhibition of MAPK-related melanoma proliferation. However, targeting of MEK can be accompanied by a time-dependent and reversible serous retinopathy of unknown origin.We analyzed the molecular mechanism by which the MEK inhibitor binimetinib may lead to retinopathy, using neuroretina and cell models of retinal pigment epithelium (RPE).Binimetinib inhibited the MAPK pathway while discontinuation of treatment resulted in reactivation. However, cell proliferation was not inhibited correspondingly during binimetinib treatment of ARPE19 cells. Remarkably, post-mitotic neuroretinal tissue displayed a strong MAPK activation that was lost after binimetinib treatment.We propose that binimetinib-associated retinopathy is correlated with inhibition of the MAPK pathway in multiple retinal components. Retinal cells are able to regain the activation after binimetinib treatment, mimicking the reversibility of the retinopathy. As most retinal cells are nonregenerating, other mechanisms than stimulation of proliferation must be involved.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4863761 | PMC |
| http://dx.doi.org/10.1097/MD.0000000000003457 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Upregulation of the MAP2K4 gene triggers endothelial-mesenchymal transition in COVID-19.
Mol Biol Rep
January 2025
Department of Molecular Biology and Genetics, Faculty of Art and Science, Tokat Gaziosmanpasa University, Tokat, 60200, Türkiye.
Background: SARS-CoV-2 infection is marked by an excessive inflammatory response, leading to elevated production of pro-inflammatory cytokines through activation of intracellular pathways like mitogen-activated protein kinase (MAPK). Viruses can use the MAPK signaling pathway to their advantage, but the relationship of this pathway to the severe SARS-CoV-2 period has not been fully elucidated. MAP2K4 is involved in the MAPK signaling pathway and affects cellular processes such as cell-cell junction, cell proliferation, differentiation and apoptosis.
View Article and Find Full Text PDFMolecular Characteristics of a Fusion Gliosarcoma: A Case Report.
Int J Surg Pathol
January 2025
Department of Pathology, Rambam Health Care Campus, Haifa, Israel.
The combination of ependymoma and gliosarcoma elements in the same tumor is extremely rare, and the molecular characteristics of these entities are not clear. Here, we present a rare aggressive brain tumor in a 12-year-old boy harboring a gene fusion, a characteristic feature of supratentorial ependymomas. On the other hand, the histopathological, molecular, and methylation profiles were compatible with a diagnosis of a mesenchymal type, IDH wild-type glioblastoma multiforme (GBM).
View Article and Find Full Text PDFPhenotypic consequences of logarithmic signaling in MAPK stress response.
iScience
January 2025
Department of Molecular Physiology and Biophysics, School of Medicine, Vanderbilt University, Nashville, TN 37232, USA.
How cells respond to dynamic environmental changes is crucial for understanding fundamental biological processes and cell physiology. In this study, we developed an experimental and quantitative analytical framework to explore how dynamic stress gradients that change over time regulate cellular volume, signaling activation, and growth phenotypes. Our findings reveal that gradual stress conditions substantially enhance cell growth compared to conventional acute stress.
View Article and Find Full Text PDFFerrostatin-1 inhibits osteoclast differentiation and prevents osteoporosis by suppressing lipid peroxidation.
J Orthop Surg Res
January 2025
Department of Orthopedics, The Second Affiliated Hospital of Harbin Medical University, No. 246 Xuefu Road, Harbin, 150001, Heilongjiang Province, China.
Background: Osteoporosis (OP) is a systemic disease characterized by low bone mass. New progress has been made in the study of OP, such as lipid peroxidation. However, the role of lipid peroxides in osteoclast differentiation is still unclear.
View Article and Find Full Text PDFConcurrent inhibition of p300/CBP and FLT3 enhances cytotoxicity and overcomes resistance in acute myeloid leukemia.
Acta Pharmacol Sin
January 2025
School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
FMS-like tyrosine kinase-3 (FLT3), a class 3 receptor tyrosine kinase, can be activated by mutations of internal tandem duplication (FLT3-ITD) or point mutations in the tyrosine kinase domain (FLT3-TKD), leading to constitutive activation of downstream signaling cascades, including the JAK/STAT5, PI3K/AKT/mTOR and RAS/MAPK pathways, which promote the progression of leukemic cells. Despite the initial promise of FLT3 inhibitors, the discouraging outcomes in the treatment of FLT3-ITD-positive acute myeloid leukemia (AML) promote the pursuit of more potent and enduring therapeutic approaches. The histone acetyltransferase complex comprising the E1A binding protein P300 and its paralog CREB-binding protein (p300/CBP) is a promising therapeutic target, but the development of effective p300/CBP inhibitors faces challenges due to inherent resistance and low efficacy, often exacerbated by the absence of reliable clinical biomarkers for patient stratification.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!