Montelukast as a novel therapeutic approach in metastatic uveal melanoma harboring a CYSLTR2 mutation: a translational case report.

backgroundUveal melanoma (UM), the most common primary intraocular malignancy in adults, has limited systemic treatment options in the metastatic setting. Recent insights into cysteinyl leukotriene receptors (CysLTRs)-particularly CYSLTR2 mutations (prevalence 2%-4%)-suggest new therapeutic approaches for patients who progress despite standard therapies. CASE: We report the case of a 59-year-old male with metastatic UM harboring a CYSLTR2 mutation. The patient experienced progression after multiple systemic treatments, including immune checkpoint inhibitors (ipilimumab/nivolumab, pembrolizumab), chemotherapy (dacarbazine, gemcitabine/treosulfan), and local radiotherapy. Lacking human leukocyte antigen-A∗02:01, he was ineligible for tebentafusp. In November 2022, next-generation sequencing identified a CYSLTR2 mutation. Based on molecular tumor board recommendation, off-label treatment with montelukast, a selective CysLT1 receptor antagonist, was initiated in March 2024. At that time, the patient had widespread metastases. Montelukast led to sustained disease stabilization for >12 months, with excellent tolerability and no reported adverse events. The observed effect may be explained by inhibition of CYSLTR1 and modulation of CYSLTR2 signaling in the mutated receptor context.

conclusionThis is the first published case suggesting a potential role for leukotriene receptor antagonists in CYSLTR2-mutant UM. These findings support further preclinical and clinical investigation of montelukast as a repurposed therapy in this challenging disease entity.