Modelling targeted therapy efficacy in NRAS mutant conjunctival melanoma

Area of Science:

• Ophthalmology
• Oncology
• Genetics

Background:

• Conjunctival melanoma (CoM) is an ultra-rare, aggressive ocular malignancy.
• CoM differs significantly from cutaneous melanoma in pathogenesis, genetics, treatment response, and prognosis.
• Therapeutic options for metastatic CoM are limited, especially for immune checkpoint therapy-resistant cases.

Purpose of the Study:

• To evaluate novel cancer therapies in metastatic CoM.
• To assess the efficacy of targeted therapies in an immune checkpoint therapy-resistant CoM case.
• To explore the feasibility of ex vivo drug testing for CoM.

Main Methods:

• Integrated functional ex vivo and molecular analysis of a metastatic CoM case.
• High-throughput drug screening using a CoM cell line against NRAS mutant cutaneous melanomas.
• Analysis of genetic mutations including NRAS, FBXW7, TERT, and TP53.

Main Results:

• PARP, MEK, and RAS(ON) inhibitors showed ex vivo efficacy in a CoM case with NRAS, FBXW7, TERT, and TP53 mutations.
• Combinatorial chemotherapy led to a partial response, followed by sustained benefit with MEK inhibitor treatment.
• Ex vivo drug testing demonstrated feasibility for CoM, with MEK and RAS inhibitors showing promise.

Conclusions:

• Functional ex vivo drug testing is feasible in conjunctival melanoma.
• Targeted therapies, including MEK and RAS inhibitors, show potential for NRAS-mutant CoM.
• Further studies are warranted for larger cohorts of NRAS-mutant conjunctival melanomas.