title: Loss of MAPK Pathway Activation in Post-Mitotic Retinal Cells as Mechanism in MEK Inhibition-Related Retinopathy in Cancer Patients.
abstract: 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.
authors.affiliation: From the Department of Ophthalmology (EHCVD, DEMD, MV, GPML, MJDL, CJFB, PAVDV), Leiden University Medical Center, Leiden; Department of Ophthalmology (AABB); Department of Clinical Genetics (AABB), Academic Medical Center; Department of Clinical and Molecular Ophthalmogenetics (AABB), The Netherlands Institute for Neurosciences/Royal Netherlands Academy of Arts and Sciences, Amsterdam; and Department of Medical Oncology (EWK), Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Elon H C
authors.initials: EHC
authors.lastname: van Dijk
authors.forename: Danique E M
authors.initials: DEM
authors.lastname: Duits
authors.forename: Mieke
authors.initials: M
authors.lastname: Versluis
authors.forename: Gregrorius P M
authors.initials: GPM
authors.lastname: Luyten
authors.forename: Arthur A B
authors.initials: AAB
authors.lastname: Bergen
authors.forename: Ellen W
authors.initials: EW
authors.lastname: Kapiteijn
authors.forename: Mark J
authors.initials: MJ
authors.lastname: de Lange
authors.forename: Camiel J F
authors.initials: CJF
authors.lastname: Boon
authors.forename: Pieter A
authors.initials: PA
authors.lastname: van der Velden
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects; D001562:Benzimidazoles / Q000008:administration & dosage / Q000009:adverse effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009362:Neoplasm Metastasis; D012164:Retinal Diseases / Q000139:chemically induced / Q000378:metabolism; D055213:Retinal Pigment Epithelium / Q000187:drug effects / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001562:Benzimidazoles; C581313:binimetinib; D020928:Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases