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Kayleigh Slater, Aisling Heeran, Mays Helmi, Helen Kalirai, Sarah E Coupland, Alberto Villanueva, Rosa Bosch, Lasse Jensen, Josep Piulats, Jacintha O'Sullivan, Breandan N Kennedy; Cysteinyl leukotriene receptor 1 (CysLT1) is associated with clinical parameters of uveal melanoma and CysLT receptor antagonists inhibit cancer hallmarks in vitro and in vivo. Invest. Ophthalmol. Vis. Sci. 2020;61(7):2849.
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Cysteinyl leukotriene receptor dysregulation is associated with a poor prognosis in various cancers. Additionally, CYSLTR2 is a uveal melanoma (UM) oncogene in 4% of patients. This research investigates the expression and tumorigenic nature of the G-protein coupled cysteinyl leukotriene receptors (CysLT1 and CysLT2) in UM and explores their potential as therapeutic targets.
Western blot and qPCR examined expression of both receptors in primary and metastatic UM cell lines (n≥3) Mel285, Mel270 and OMM2.5. Immunohistochemical staining on UM patient samples (n = 50) analysed expression of both receptors and their relationship to matched patient clinical data. The effect of cysteinyl leukotriene receptor targeting drugs (10 - 50 μM) on UM cell survival and proliferation (n≥3) was analysed. The three highest-ranking drugs were tested in zebrafish cell line xenograft models and Seahorse metabolism assays to elucidate their effects on cancer hallmarks.
CysLT1 and CysLT2 are expressed in all UM cell lines and patient tumours analysed. Interestingly, high CysLT1 expression has a statistically significant association with ciliary body involvement (p =0.041), a poor prognostic indicator in the disease. Similarly, this receptor showed a trend towards high expression and poor patient survival but did not reach statistical significance (p = 0.122). Drugs that specifically target CysLT1, but not those targeting CysLT2, significantly block long-term cell proliferation and inhibit oxidative phosphorylation, but not glycolysis, in a variety of UM cell lines or zebrafish xenograft models.
CysLT1 and CysLT2 receptors are expressed in UM patient samples and cell lines and an association between high CysLT1 expression and clinical parameters was identified. In addition, targeting of CysLT1, but not CysLT2, in UM is effective both in vitro and in vivo. We are currently developing cell line and patient-derived xenograft models of UM.
This is a 2020 ARVO Annual Meeting abstract.
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