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

Jasmine H Francis1,2, William Foulsham1,2, Julia Canestraro1

  • 1Ophthalmic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Ocular Oncology and Pathology
|February 20, 2024
PubMed
Abstract

Insights

Mitogen-activated pathway kinase (MAPK) inhibitors can cause retinopathy. This study found that inhibiting downstream targets like MEK or ERK leads to more severe retinal fluid accumulation than inhibiting upstream FGFR signaling.

Area of Science:

  • Oncology
  • Ophthalmology
  • Pharmacology

Background:

  • Mitogen-activated pathway kinase (MAPK) pathway is a therapeutic target in many cancers.
  • MAPK inhibitors can cause adverse effects, including retinopathy.
  • Different MAPK inhibitors target various points in the pathway, potentially leading to varied side effects.

Purpose of the Study:

  • To compare the clinical and morphological characteristics of serous retinal disturbances in patients receiving MAPK inhibitors with variable pathway inhibition.
  • To investigate differences in retinopathy severity based on the specific MAPK pathway target (FGFR, MEK, or ERK).

Main Methods:

  • Retrospective observational study of prospectively collected data from a single tertiary oncology referral center.
  • Included 65 patients (128 eyes) with metastatic cancer treated with FGFR, MEK, or ERK inhibitors, confirmed retinopathy via optical coherence tomography (OCT).
  • Compared baseline OCT with treatment-emergent choroid/retinal OCT abnormalities.

Main Results:

  • Retinopathy manifested as bilateral, fovea-involving, reversible subretinal fluid foci across all drug classes.
  • Retinopathy was least common, least severe, and least symptomatic with upstream FGFR inhibitors.
  • Retinopathy was most common, most severe (more fluid foci, expansive configurations), and most symptomatic with downstream MEK or ERK inhibitors.

Conclusions:

  • MAPK pathway inhibitors can induce subretinal fluid foci with distinct characteristics based on the targeted protein (FGFR, MEK, ERK).
  • Inhibiting the MAPK pathway further downstream results in a higher incidence, greater severity, and increased symptomatology of retinopathy.
Keywords:
Extracellular signal-regulated inhibitorFibroblast growth factor receptor inhibitorMitogen-activated protein kinase inhibitorRetina

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