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).