Modelling targeted therapy efficacy in NRAS mutant conjunctival melanoma

Conjunctival melanoma (CoM) is an ultra-rare ocular melanoma that originates from transformed melanocytes of the conjunctiva. CoM shares a common embryonic cell of origin as cutaneous melanoma and manifests as highly aggressive malignancy. Despite cellular similarity of conjunctival and cutaneous melanoma, the pathogenesis, genetic landscape, response to treatment, and prognosis of these malignancies differ significantly. Immune checkpoint therapy has shown promise in individual CoM cases, but therapeutic options for metastatic CoM remain limited. To evaluate efficacy of the latest novel cancer therapies in metastatic CoM, we performed an integrated functional ex vivo and molecular analysis in an immune checkpoint therapy resistant metastatic CoM case. PARP, MEK and RAS(ON) inhibitors along select standard chemotherapies including cisplatin and docetaxel displayed marked ex vivo efficacy in NRAS, FBXW7, TERT and TP53 mutated genetic background. Following molecular tumor board evaluation, the patient received combinatorial chemotherapy as part of standard therapy resulting in a clinical partial response. Upon progression, MEK inhibitor treatment was selected for treatment, resulting in sustained clinical benefit correlating with the ex vivo observed sensitivity. To provide further insights on efficacy of latest experimental cancer therapies including TEAD, pan-RAS/RAF and the RAS(ON) inhibitors in NRAS mutant CoM, a spontaneously immortal cell line established from the patient's tumor was used for comparative high-throughput screening against two NRAS mutant cutaneous melanomas. Results of our study demonstrate feasibility of functional ex vivo drug testing in conjunctival melanoma and warrant further studies of targeted therapies including MEK and RAS inhibitors in larger cohorts of NRAS mutant conjunctival melanomas.