MAPK Pathway Drugs and Ocular Toxicity

Tovorafenib (Ojemda), a pan-RAF kinase inhibitor approved for pediatric [low-grade glioma](https://www.openevidence.com/rare-disease/low-grade-astrocytoma), is associated with several ocular adverse events:

• MEK inhibitor-associated retinopathy (MEKAR) — serous retinal detachment and retinal pigment epithelium (RPE) changes*
• Photosensitivity — patients are advised to wear sunglasses*
• Periorbital edema*
• Blurred vision*

These effects are considered a class effect of MAPK pathway inhibition, particularly due to downstream suppression of ERK signaling in the retinal pigment epithelium.

• MEK inhibitors carry the highest ocular risk (MEKAR, serous retinopathy, RVO), occurring in up to 90% of patients on subclinical OCT*
• BRAF inhibitors predominantly cause uveitis rather than retinopathy*
• ERK inhibitors produce MEKAR-like retinopathy with additional intraretinal edema, but events appear self-limited*
• KRAS inhibitors have minimal ocular toxicity*

The MAPK/RAS-RAF-MEK-ERK cascade is a highly conserved, three-tiered signaling pathway that transmits extracellular signals from the cell surface to the nucleus, regulating cell proliferation, differentiation, survival, and migration.

1. Extracellular stimulus → Receptor activation: Growth factors bind to receptor tyrosine kinases (RTKs) such as EGFR, triggering receptor dimerization and autophosphorylation.
2. Adaptor protein recruitment → RAS activation: Phosphorylated RTKs recruit adaptor proteins (Shc, Grb2) and the guanine nucleotide exchange factor SOS, which converts RAS from inactive (RAS-GDP) to active (RAS-GTP). Three RAS isoforms exist: HRAS, KRAS, and NRAS.
3. RAS → RAF (MAP3K tier): Active RAS-GTP recruits RAF kinases (ARAF, BRAF, CRAF) to the plasma membrane for activation. BRAF is the most potent activator and the most frequently mutated in cancer (V600E).
4. RAF → MEK (MAP2K tier): Activated RAF phosphorylates MEK1/2. MEK is the only known physiological substrate of RAF.
5. MEK → ERK (MAPK tier): Activated MEK1/2 phosphorylate ERK1/2 at the conserved TEY motif. Both phosphorylation events are required for full activation.
6. ERK → Downstream effectors: ERK1/2 phosphorylate over 250 known substrates in the cytoplasm and nucleus, activating transcription factors (Elk-1, c-Fos, c-Myc, AP-1) that drive cell cycle progression.

• Signal amplification: Each tier amplifies the signal from upstream to downstream*
• Negative feedback: ERK phosphorylates upstream components (SOS, RAF) to attenuate signaling*
• Scaffold proteins (KSR1/2, IQGAP1, MP1) organize cascade components into signaling complexes*
• Crosstalk: Cross-communication with the PI3K/AKT pathway and other MAPK cascades (JNK, p38)*

Oncogenic mutations — most commonly in KRAS (~30% of all cancers) and BRAF V600E (~7% of all cancers, ~60% of melanomas) — constitutively activate this cascade. Ocular toxicity from MAPK pathway inhibitors arises because ERK signaling is critical for retinal pigment epithelium (RPE) homeostasis; ERK loss in RPE cells leads to decreased RPE65 expression and retinal degeneration.

MAPK stands for Mitogen-Activated Protein Kinase. The name reflects the pathway's original discovery as a kinase cascade activated by mitogens — extracellular signals (such as growth factors) that stimulate cell division (mitosis).

This document uses standard DokuWiki markup conventions including:

- `======` through `====` for heading levels - `^` and `|` for table headers and rows - `text` for bold - Ordered (` -`) and unordered (` *`) lists with two-space indentation*

The content is synthesized from the sources discussed throughout this conversation, including FDA drug labels, pharmacovigilance analyses, clinical trial data, and pathway biology reviews.[1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16]

Would you like this reformatted for a different wiki system (e.g., MediaWiki or Confluence markup)?

### References

1. MEKTOVI. Food and Drug Administration. Updated date: 2025-03-20. 2. Mekinist. Food and Drug Administration. Updated date: 2026-05-07. 3. LUMAKRAS. Food and Drug Administration. Updated date: 2025-01-22. 4. Ocular Safety Profile of BRAF and MEK Inhibitors: Data From the World Health Organization Pharmacovigilance Database. Mettler C, Monnet D, Kramkimel N, et al. Ophthalmology. 2021;128(12):1748-1755. doi:10.1016/j.ophtha.2021.05.008. 5. Ocular Adverse Events Associated With BRAF and MEK Inhibitor Combination Therapy: A Pharmacovigilance Disproportionality Analysis of the FDA Adverse Event Reporting System. Huang S, Guo Z, Wang M, et al. Expert Opinion on Drug Safety. 2023;22(2):175-181. doi:10.1080/14740338.2023.2189235. 6. Adverse Events Associated With Dabrafenib, Trametinib, and Their Combination Therapy: A Disproportionality Analysis of the FDA Adverse Event Reporting System ( FAERS ) Database. Zhang Z, Wu Q, Wang Y, et al. Pharmacoepidemiology and Drug Safety. 2025;34(9):e70200. doi:10.1002/pds.70200. 7. Characterization of Serous Retinopathy Associated With Cobimetinib: Integrated Safety Analysis of Four Studies. Barteselli G, Goodman GR, Patel Y, et al. Drug Safety. 2022;45(12):1491-1499. doi:10.1007/s40264-022-01248-2. 8. Intermittent Schedules of the Oral RAF-MEK Inhibitor CH5126766/VS-6766 in Patients With RAS/RAF-mutant Solid Tumours and Multiple Myeloma: A Single-Centre, Open-Label, Phase 1 Dose-Escalation and Basket Dose-Expansion Study. Guo C, Chénard-Poirier M, Roda D, et al. The Lancet. Oncology. 2020;21(11):1478-1488. doi:10.1016/S1470-2045(20)30464-2. 9. Clinical and Morphologic Characteristics of Extracellular Signal-Regulated Kinase Inhibitor-Associated Retinopathy. Francis JH, Canestraro J, Haggag-Lindgren D, et al. Ophthalmology. Retina. 2021;5(12):1187-1195. doi:10.1016/j.oret.2021.06.001. 10. 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. Sullivan RJ, Infante JR, Janku F, et al. Cancer Discovery. 2018;8(2):184-195. doi:10.1158/2159-8290.CD-17-1119. 11. Results of a first-in-human, dose-escalation phase 1 study of the ERK1/2 inhibitor ATG-017 in patients with advanced solid tumors. Wahlroos S, Teng C, Tran B, et al. Journal of Clinical Oncology. 2024;42(Suppl 16):e15114. doi:10.1200/JCO.2024.42.16_suppl.e15114. 12. RAF-MEK-ERK Pathway in Cancer Evolution and Treatment. Ullah R, Yin Q, Snell AH, Wan L. Seminars in Cancer Biology. 2022;85:123-154. doi:10.1016/j.semcancer.2021.05.010. 13. The MEK/ERK Network as a Therapeutic Target in Human Cancer. Barbosa R, Acevedo LA, Marmorstein R. Molecular Cancer Research : MCR. 2021;19(3):361-374. doi:10.1158/1541-7786.MCR-20-0687. 14. Targeting ERK beyond the boundaries of the kinase active site in melanoma. Sammons RM, Ghose R, Tsai KY, Dalby KN. Molecular Carcinogenesis. 2019;58(9):1551-1570. doi:10.1002/mc.23047. 15. Targeting the Raf-Mek-Erk Mitogen-Activated Protein Kinase Cascade for the Treatment of Cancer. Roberts PJ, Der CJ. Oncogene. 2007;26(22):3291-310. doi:10.1038/sj.onc.1210422. 16. ERK1/2 MAP Kinases: Structure, Function, and Regulation. Roskoski R. Pharmacological Research. 2012;66(2):105-43. doi:10.1016/j.phrs.2012.04.005.