Log in to MyKarger to check if you already have access to this content.

Buy FullText & PDF Unlimited re-access via MyKarger Unrestricted printing, no saving restrictions for personal use read more

CHF 38.00 *
EUR 35.00 *
USD 39.00 *

Select

KAB

Buy a Karger Article Bundle (KAB) and profit from a discount!

If you would like to redeem your KAB credit, please log in.

Save over 20% compared to the individual article price.

Learn more

Rent via DeepDyve Unlimited fulltext viewing of this article Organize, annotate and mark up articles Printing and downloading restrictions apply

Start free trial

Subscribe Access to all articles of the subscribed year(s) guaranteed for 5 years Unlimited re-access via Subscriber Login or MyKarger Unrestricted printing, no saving restrictions for personal use read more

Subcription rates

Select

* The final prices may differ from the prices shown due to specifics of VAT rules.

Article / Publication Details

Received: March 22, 2022
Accepted: December 22, 2022
Published online: February 08, 2023

Number of Print Pages: 7
Number of Figures: 2
Number of Tables: 2

ISSN: 2296-4681 (Print)
eISSN: 2296-4657 (Online)

For additional information: https://www.karger.com/OOP

Abstract

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 morphological 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, and 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). Conclusion: This study shows MAPK pathway inhibitors may cause subretinal fluid foci with unique clinical and morphological 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.

© 2023 S. Karger AG, Basel

References Akinleye A, Furqan M, Mukhi N, Ravella P, Liu D. MEK and the inhibitors: from bench to bedside. J Hematol Oncol. 2013 Apr 12;6:27. Fouladi M, Stewart CF, Blaney SM, Onar-Thomas A, Schaiquevich P, Packer RJ, et al. A molecular biology and phase II trial of lapatinib in children with refractory CNS malignancies: a pediatric brain tumor consortium study. J Neurooncol. 2013 Sep;114(2):173–9. Turner MC, Rossfeld K, Salama AKS, Tyler D, Beasley G. Can binimetinib, encorafenib and masitinib be more efficacious than currently available mutation-based targeted therapies for melanoma treatment?Expert Opin Pharmacother. 2017 Apr;18(5):487–95. Dummer R, Schadendorf D, Ascierto PA, Arance A, Dutriaux C, Di Giacomo AM, et al. Binimetinib versus dacarbazine in patients with advanced NRAS-mutant melanoma (NEMO): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2017 Apr;18(4):435–45. Suresh PS, Jairam RK, Chandrasekhar DV, Vinod AB, Hiremath RA, Raj A, et al. Prediction of human pharmacokinetics of ulixertinib, a novel ERK1/2 inhibitor from mice, rats, and dogs pharmacokinetics. Eur J Drug Metab Pharmacokinet. 2018 Aug;43(4):453–60. Sullivan RJ, Infante JR, Janku F, Wong DJL, Sosman JA, Keedy V, et al. First-in-Class ERK1/2 inhibitor ulixertinib (BVD-523) in patients with MAPK mutant advanced solid tumors: results of a phase I dose-escalation and expansion study. Cancer Discov. 2018 Feb;8(2):184–95. Francis JH, Habib LA, Abramson DH, Yannuzzi LA, Heinemann M, Gounder MM, et al. Clinical and morphologic characteristics of MEK inhibitor-associated retinopathy: differences from central serous chorioretinopathy. Ophthalmology. 2017 Dec;124(12):1788–98. Francis JH, Canestraro J, Haggag-Lindgren D, Harding JJ, Diamond EL, Drilon A, et al. Clinical and morphologic characteristics of extracellular signal-regulated kinase inhibitor-associated retinopathy. Ophthalmol Retina. 2021 Jun 5;5(12):1187–95. Francis JH, Harding JJ, Schram AM, Canestraro J, Haggag-Lindgren D, Heinemann M, et al. Clinical and morphologic characteristics of fibroblast growth factor receptor inhibitor-associated retinopathy. JAMA Ophthalmol. 2021 Sep 2;139(10):1126–30. Wacker B, Nagrani T, Weinberg J, Witt K, Clark G, Cagnoni PJ. Correlation between development of rash and efficacy in patients treated with the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib in two large phase III studies. Clin Cancer Res. 2007 Jul 1;13:3913–21. van Dijk EHC, Duits DEM, Versluis M, Luyten GPM, Bergen AAB, Kapiteijn EW, et al. Loss of MAPK pathway activation in post-mitotic retinal cells as mechanism in MEK inhibition-related retinopathy in cancer patients. Medicine (Baltimore). 2016 May;95(18):e3457. Guillonneau X, Régnier-Ricard F, Laplace O, Jonet L, Bryckaert M, Courtois Y, et al. Fibroblast growth factor (FGF) soluble receptor 1 acts as a natural inhibitor of FGF2 neurotrophic activity during retinal degeneration. Mol Biol Cell. 1998 Oct;9(10):2785–802. Kyosseva SV. Targeting MAPK signaling in age-related macular degeneration. Ophthalmol Eye Dis. 2016;8:23–30. Article / Publication Details

Received: March 22, 2022
Accepted: December 22, 2022
Published online: February 08, 2023

Number of Print Pages: 7
Number of Figures: 2
Number of Tables: 2

ISSN: 2296-4681 (Print)
eISSN: 2296-4657 (Online)

For additional information: https://www.karger.com/OOP