Using Patient iPSC-derived Retinal Pigment Epithelial Cells to Evaluate Differential Susceptibility to MEK Inhibitor-Associated Retinopathy

Lola P Lozano; Timothy M Boyce; Andrew P Groves; Henry L Keen; Culver Boldt; Robert F Mullins; Elaine M Binkley; Budd A Tucker

doi:10.64898/2026.04.11.717944

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Using Patient iPSC-derived Retinal Pigment Epithelial Cells to Evaluate Differential Susceptibility to MEK Inhibitor-Associated Retinopathy

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Using Patient iPSC-derived Retinal Pigment Epithelial Cells to Evaluate Differential Susceptibility to MEK Inhibitor-Associated Retinopathy

Lola P Lozano, Timothy M Boyce, Andrew P Groves, Henry L Keen, Culver Boldt, Robert F Mullins, Elaine M Binkley and Budd A Tucker

bioRxiv

Cold Spring Harbor Laboratory

04/14/2026

DOI: 10.64898/2026.04.11.717944

PMCID: PMC13104921

PMID: 42039655

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https://doi.org/10.64898/2026.04.11.717944View

Preprint (Author's original) This preprint has not been evaluated by subject experts through peer review. Preprints may undergo extensive changes and/or become peer-reviewed journal articles. Open Access

Abstract

Compare the effect of MEK inhibition on iPSC-derived retinal pigmental epithelial (RPE) cells generated from a patient who developed MEK inhibitor-Associated Retinopathy (MEKAR) versus a patient who did not develop retinopathy. Case-control. Two female patients with Neurofibromatosis Type 1 who were treated with MEK inhibitors. One patient developed MEKAR, the other did not. RPE were generated from human induced pluripotent stem cells (hiPSCs) from these two patients. These hiPSC-derived RPE were treated with selumetinib for 10 days. Phagocytic activity and changes in gene expression. As previously reported, there was a significant increase in internalized rhodopsin in phagocytosis assays, yet this was only found in hiPSC-derived RPE from the patient who developed MEKAR. Selumetinib decreased expression of genes related to fluid transport and cell volume, including aquaporins and solute transporters. At baseline, cells from the patients without MEKAR had higher expression of these genes. Interestingly, selumetinib-induced changes in gene expression only reached statistical significance in cells from the patient who did not develop MEKAR, suggesting these changes may be a compensatory protective mechanism. Patients susceptible to forming MEKAR may have increased phagocytosis without a compensatory change in expression of genes related to fluid flux, thereby inhibiting their ability to transport fluid out of the subretinal space. MEK inhibitor-Associated Retinopathy may only affect susceptible patients whose retinal pigment epithelium cannot sufficiently regulate expression of genes related to fluid transport and cell volume, altering the ability of these cells to properly function.

Details

Title: Subtitle: Using Patient iPSC-derived Retinal Pigment Epithelial Cells to Evaluate Differential Susceptibility to MEK Inhibitor-Associated Retinopathy
Creators: Lola P Lozano - University of Iowa
Timothy M Boyce - University of Iowa
Andrew P Groves - University of Iowa
Henry L Keen - University of Iowa
Culver Boldt
Robert F Mullins - University of Iowa
Elaine M Binkley - University of Iowa
Budd A Tucker - University of Iowa
Resource Type: Preprint
Publication Details: bioRxiv
DOI: 10.64898/2026.04.11.717944
PMID: 42039655
PMCID: PMC13104921
NLM abbreviation: bioRxiv
ISSN: 2692-8205
eISSN: 2692-8205
Publisher: Cold Spring Harbor Laboratory; United States
Language: English
Date posted: 04/14/2026
Academic Unit: Stead Family Department of Pediatrics; The University of Iowa Institute for Vision Research; Hematology/Oncology; Neuroscience and Pharmacology; Ophthalmology and Visual Sciences; Iowa Institute of Human Genetics
Record Identifier: 9985157630502771

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