Preprint
Modeling MEK inhibitor-Associated Retinopathy in vitro using human induced pluripotent stem cell-derived retinal pigment epithelial cells
bioRxiv
10/05/2025
DOI: 10.1101/2025.10.03.680301
PMCID: PMC12621998
PMID: 41256480
Abstract
Pharmacologic inhibitors of MEK are important anti-cancer drugs but can result in MEK inhibitor-Associated Retinopathy (MEKAR) in which vision is lost due to serous retinal detachments that form via an unknown mechanism. We hypothesized that the cause of this side effect is drug-induced dysfunction of retinal pigment epithelial (RPE) cells. To test this hypothesis, we used human induced pluripotent stem cell-derived RPE cells. We treated mature, hiPSC-derived RPE cells with selumetinib and measured impacts on RPE-specific function, structure, and gene expression. Selumetinib increases the ability of hiPSC-derived RPE to internalize bovine rod outer segments (1.9 vs 3.0, p=0.0024). It also decreases expression of aquaporin 1 during the first 10 days of treatment (2.7 vs 1.1, p=0.0015). It has no effect on the ability of hiPSC-derived RPE to maintain membrane integrity. Selumetinib alters gene expression of hiPSC-derived RPE, with significant changes in genes involved in transport of ions and small molecules regulating cell volume and lysosomal acidification. Selumetinib may lead to subretinal fluid accumulation by both increasing secretions into this space and decreasing outflow.Pharmacologic inhibitors of MEK are important anti-cancer drugs but can result in MEK inhibitor-Associated Retinopathy (MEKAR) in which vision is lost due to serous retinal detachments that form via an unknown mechanism. We hypothesized that the cause of this side effect is drug-induced dysfunction of retinal pigment epithelial (RPE) cells. To test this hypothesis, we used human induced pluripotent stem cell-derived RPE cells. We treated mature, hiPSC-derived RPE cells with selumetinib and measured impacts on RPE-specific function, structure, and gene expression. Selumetinib increases the ability of hiPSC-derived RPE to internalize bovine rod outer segments (1.9 vs 3.0, p=0.0024). It also decreases expression of aquaporin 1 during the first 10 days of treatment (2.7 vs 1.1, p=0.0015). It has no effect on the ability of hiPSC-derived RPE to maintain membrane integrity. Selumetinib alters gene expression of hiPSC-derived RPE, with significant changes in genes involved in transport of ions and small molecules regulating cell volume and lysosomal acidification. Selumetinib may lead to subretinal fluid accumulation by both increasing secretions into this space and decreasing outflow.
Details
- Title: Subtitle
- Modeling MEK inhibitor-Associated Retinopathy in vitro using human induced pluripotent stem cell-derived retinal pigment epithelial cells
- Creators
- Lola P Lozano - University of IowaMadeleine Jennisch - University of IowaRenato JensenJason A Ratcliff - University of IowaLuke A Wiley - University of IowaBrynnon Harman - University of IowaMegan J Riker - University of IowaAllison T Wright - University of IowaBradley A Erickson - University of Iowa, UrologyH Culver Boldt - University of IowaTimothy M Boyce - University of IowaRobert F Mullins - University of IowaElaine M Binkley - University of IowaBudd A Tucker - University of Iowa
- Resource Type
- Preprint
- Publication Details
- bioRxiv
- DOI
- 10.1101/2025.10.03.680301
- PMID
- 41256480
- PMCID
- PMC12621998
- NLM abbreviation
- bioRxiv
- ISSN
- 2692-8205
- eISSN
- 2692-8205
- Language
- English
- Date posted
- 10/05/2025
- Academic Unit
- The University of Iowa Institute for Vision Research; Neuroscience and Pharmacology; Urology; Internal Medicine; Ophthalmology and Visual Sciences; Iowa Institute of Human Genetics
- Record Identifier
- 9985033763902771
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