Clinical and Morphologic Characteristics of Extracellular Signal-Regulated Kinase Inhibitor-Associated Retinopathy

Francis, Jasmine H.; Canestraro, Julia; Haggag-Lindgren, Dianna; Harding, James J.; Diamond, Eli L.; Drilon, Alexander; Li, Bob T.; Iyer, Gopa; Schram, Alison M.; Abramson, David H.

doi:10.1016/j.oret.2021.06.001

Cited by 9 publications

(5 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Very similar clinical manifestations, but with an increased occurrence of concomitant intraretinal fluid, have also been observed in patients receiving ERK inhibitors, effects that also did not cause irreversible loss of vision or serious eye damage and that did not require medical intervention [224]. It is worth mentioning that these clinical manifestations were observed in patients under ERK inhibitor treatment for metastatic cancer, and not any ocular disease.…”

Section: Mapk Inhibitoradverse Effectssupporting

confidence: 59%

MAPK Pathways in Ocular Pathophysiology: Potential Therapeutic Drugs and Challenges

Moustardas

Aberdam

Lagali

2023

Cells

View full text Add to dashboard Cite

Mitogen-activated protein kinase (MAPK) pathways represent ubiquitous cellular signal transduction pathways that regulate all aspects of life and are frequently altered in disease. Once activated through phosphorylation, these MAPKs in turn phosphorylate and activate transcription factors present either in the cytoplasm or in the nucleus, leading to the expression of target genes and, as a consequence, they elicit various biological responses. The aim of this work is to provide a comprehensive review focusing on the roles of MAPK signaling pathways in ocular pathophysiology and the potential to influence these for the treatment of eye diseases. We summarize the current knowledge of identified MAPK-targeting compounds in the context of ocular diseases such as macular degeneration, cataract, glaucoma and keratopathy, but also in rare ocular diseases where the cell differentiation, proliferation or migration are defective. Potential therapeutic interventions are also discussed. Additionally, we discuss challenges in overcoming the reported eye toxicity of some MAPK inhibitors.

show abstract

Section: Mapk Inhibitoradverse Effectssupporting

confidence: 59%

MAPK Pathways in Ocular Pathophysiology: Potential Therapeutic Drugs and Challenges

Moustardas

Aberdam

Lagali

2023

Cells

View full text Add to dashboard Cite

show abstract

“…Additional demographics and patient-specific data were extracted retrospectively under an IRB approved protocol. One-hundred twentyeight eyes exhibited subretinal fluid on optical coherence tomography (OCT; previously published [7][8][9]) and were compared in the present study.…”

Section: Methodsmentioning

confidence: 99%

“…In an effort to better understand this topic, this study systematically compared drug-induced retinopathy observed in patients undergoing FGFR, MEK, or ERK inhibitor treatment within prospective clinical trials. Data were pooled from previously published series on FGFR, MEK, or ERK inhibitor retinopathy [7][8][9] to explore differences among drug types with the intent of bringing ophthalmologists and oncologists a step forward to better balance benefits and harms of these drugs. In the present study, clinical and morphological characteristics were compared across patients receiving FGFFR, MEK, or ERK inhibition, along with the associated retinal, RPE, and choroidal changes of the fluid foci that were then compared with the drug-induced retinopathy.…”

Section: Introductionmentioning

confidence: 99%

Mitogen-Activated Pathway Kinase Inhibitor-Associated Retinopathy: Do Features Differ with Upstream versus Downstream Inhibition?

et al. 2023

View full text Add to dashboard Cite

Introduction Many cancers have derangement of the Mitogen-Activated Pathway Kinase (MAPK) making this pathway blockade a therapeutic target. However, inhibitors of MAPK can result in adverse effects including retinopathy. This study compares clinical and morphologic characteristics of serous retinal disturbances in patients taking agents with variable inhibition of MAPK: either direct interference of mitogen-activated protein kinase kinase (MEK) or extracellular signal-regulated kinase (ERK) inhibitors or with indirect inhibition via interference with FGFR signaling. Methods This retrospective observational study of prospectively collected pooled data is from a single tertiary oncology referral center. Of 339 patients receiving MAPK inhibitors (171, 107, 61 on FGFR, MEK and ERK inhibitors, respectively) for treatment of metastatic cancer, this study included 128 eyes of 65 patients with evidence of retinopathy confirmed by optical coherence tomography (OCT). The main outcome was characteristics of treatment-emergent choroid/retinal OCT abnormalities as compared to baseline OCT Results In all patients on one of three drug classes (FGFRi, MEKi, ERKi) the retinopathy manifested as subretinal fluid foci that were bilateral, fovea-involving and reversible without intervention. There were notable differences between the three classes of drugs: the proportion of patients with retinopathy, number of fluid foci per eye, proportion of eyes with intraretinal edema and the proportion of symptomatic patients was least for the upstream target (FGFR inhibitors) and greatest for the downstream targets (MEK or ERK inhibitors). Discussion/conclusion This study shows MAPK pathway inhibitors may cause subretinal fluid foci with unique clinical and morphologic characteristics depending on the target (FGFR, MEK or ERK) implicated. Retinopathy is more common, more symptomatic and more severe (more fluid foci, more expansive fluid configurations) the further downstream the MAPK pathway is inhibited.

show abstract

“…The therapeutic efficacy of MEKi has been demonstrated in various types of metastatic cancer [ 1 , 3 , 5 ], but adverse events including diarrhea, nausea, and visual disturbances due to serous retinal detachments (SRDs) are frequently associated with MEKi treatment. In a clinical trial of a MEKi for metastatic malignant melanoma, the reported incidence of SRD was high at 77% [ 5 , 6 ]. Multiple SRDs that appear and resolve rapidly along with MEKi administration and cessation are the characteristic feature of MEKi-associated retinopathy, and fortunately, the visual prognosis is fair with vision deterioration developing only in 23% of the clinical trial patients, and the deterioration did not lead to permanent vision loss [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

“…A striking feature of MEKi-associated SRD is the lack of leakage from either the retinal vessels or the retinal pigment epithelium (RPE), meaning choroid in fluorescein and indocyanine angiography (FA/IA) [ 2 , 3 , 4 , 6 , 7 , 8 , 10 ]. Typical multiple SRD lesions associated with other retinochoroidal diseases (e.g., central serous chorioretinopathy [CSC]) are accompanied by fluorescein leakage [ 4 , 9 ].…”

Section: Introductionmentioning

confidence: 99%

Serous Retinal Detachment without Leakage on Fluorescein/Indocyanine Angiography in MEK Inhibitor-Associated Retinopathy

Murata

Murakami

Fukui

et al. 2022

Case Rep Ophthalmol

View full text Add to dashboard Cite

The aim of this paper was to report the cases of 3 consecutive patients with mitogen-activated protein kinase kinase inhibitor (MEKi)-associated retinopathy with characteristic multiple serous retinal detachments (SRDs). A functional analysis of the retinal pigment epithelium was performed in 2 patients by electro-oculography (EOG). In all 3 patients, SRD lesions were observed in the posterior pole including the fovea of both eyes. Interestingly, neither obvious leakage in fluorescein/indocyanine angiography nor abnormal fundus autofluorescence was associated. SRDs and associated cystoid macular edema in one case rapidly resolved with the cessation of MEKi but recurred quickly after treatment resumption. In EOG tests, three of four eyes with multiple SRDs showed a marked decrease in the light-peak-to-dark-trough ratio (LP:DT ratio). The LP:DT ratio in EOG reflects the transepithelial potential of the retinal pigment epithelium, suggesting the involvement of disrupted tight junctions and impaired active transport of fluid/ions in MEKi-associated retinopathy. The latter may be the major cause of SRDs as we observed that fluid leakage in angiography was absent in the areas of the patients' SRDs.

show abstract

Clinical and Morphologic Characteristics of Extracellular Signal-Regulated Kinase Inhibitor-Associated Retinopathy

Cited by 9 publications

References 16 publications

MAPK Pathways in Ocular Pathophysiology: Potential Therapeutic Drugs and Challenges

MAPK Pathways in Ocular Pathophysiology: Potential Therapeutic Drugs and Challenges

Mitogen-Activated Pathway Kinase Inhibitor-Associated Retinopathy: Do Features Differ with Upstream versus Downstream Inhibition?

Serous Retinal Detachment without Leakage on Fluorescein/Indocyanine Angiography in MEK Inhibitor-Associated Retinopathy

Contact Info

Product

Resources

About