Targeting of the MAPK and AKT pathways in conjunctival melanoma shows potential synergy

Area of Science:

• Ophthalmology
• Oncology
• Molecular Biology

Background:

• Conjunctival melanoma (CM) is a rare but aggressive ocular cancer.
• Activating mutations in BRAF and NRAS are common in CM, similar to cutaneous melanoma.
• The mitogen-activated protein kinase (MAPK) and AKT pathways are crucial in melanoma cell signaling.

Purpose of the Study:

• To investigate the expression of MAPK and AKT pathway targets in conjunctival melanocytic lesions.
• To evaluate the efficacy of specific pathway inhibitors in suppressing CM growth in vitro.
• To determine if BRAF, NRAS, MEK, or AKT inhibitors could be potential therapeutic targets for CM.

Main Methods:

• Immunohistochemistry was used to assess BRAF V600E mutation and phosphorylated ERK (p-ERK) and AKT (p-AKT) expression in 131 conjunctival lesions.
• Three CM cell lines were treated with BRAF inhibitors (Vemurafenib, Dabrafenib), a MEK inhibitor (MEK162), and an AKT inhibitor (MK2206).
• Cell proliferation, phosphorylation, cell cycling, and apoptosis were analyzed to assess drug efficacy.

Main Results:

• BRAF V600E mutation was found in 19% of nevi and 26% of melanomas.
• p-ERK and p-AKT were expressed in all conjunctival lesions, indicating pathway activation.
• BRAF inhibitors reduced CM cell growth, while MEK and AKT inhibitors demonstrated dose-dependent proliferation inhibition. A combination of MEK and AKT inhibitors resulted in synergistic growth inhibition and cell death.

Conclusions:

• Constitutive activation of ERK and AKT pathways is present in various conjunctival melanocytic lesions, including melanoma.
• BRAF inhibitors showed efficacy in growth inhibition but were not consistently cytotoxic.
• Combined MEK and AKT inhibition demonstrated significant anti-tumor effects, suggesting a promising therapeutic strategy for metastatic conjunctival melanoma.