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High Cysteinyl Leukotriene Receptor 1 Expression Correlates with Poor Survival of Uveal Melanoma Patients and Cognate Antagonist Drugs Modulate the Growth, Cancer Secretome, and Metabolism of Uveal Melanoma Cells

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UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, D04 V1W8 Dublin, Ireland
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Genomics Medicine Ireland Limited, Cherrywood Business Park Building 4, D18 K7W4 Dublin, Ireland
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Trinity Translational Medicine Institute, Department of Surgery, Trinity College Dublin, St. James’s Hospital, D08 W9RT Dublin, Ireland
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Unit of Biomarkers and Susceptibility, Oncology Data Analytics Program (ODAP), Catalan Institute of Oncology (ICO), Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL) and CIBERESP, L’Hospitalet de Llobregat, 08908 Barcelona, Spain
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Department of Clinical Sciences, Faculty of Medicine and Health Sciences, University of Barcelona, 08036 Barcelona, Spain
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Liverpool Ocular Oncology Research Group, Department of Molecular and Clinical Cancer Medicine, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L7 8TX, UK
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Unit of Cardiovascular Medicine, Division of Diagnostics and Specialist Medicine, Department of Health, Medical and Caring Sciences, Linköping University, SE-581 83 Linköping, Sweden
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Xenopat S.L., Parc Científic de Barcelona, Baldiri Reixac, 15-21 Edifici Hèlix, 08028 Barcelona, Spain
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Medical Oncology Department, Catalan Institute of Cancer (ICO), IDIBELL-OncoBell, Hospitalet de Llobregat, 08908 Barcelona, Spain
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Clinical Research in Solid Tumors Group (CREST), Bellvitge Biomedical Research Institute IDIBELL-OncoBell, CIBERONC, Hospitalet de Llobregat, 08908 Barcelona, Spain
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Liverpool Clinical Laboratories, Liverpool University Hospitals NHS Foundation Trust, Liverpool L69 3GA, UK
*
Author to whom correspondence should be addressed.
Cancers 2020, 12(10), 2950; https://doi.org/10.3390/cancers12102950
Received: 20 August 2020 / Revised: 4 October 2020 / Accepted: 5 October 2020 / Published: 13 October 2020
This research investigates the disease relevance and therapeutic potential of cysteinyl leukotriene receptors in uveal melanoma (UM), a rare eye cancer that often spreads to the liver. Unfortunately, there are no therapies available to stop the spread of UM and patients are often faced with an extremely poor prognosis. We assess whether the cysteinyl leukotriene receptors (CysLT1 and CysLT2) are relevant to the progression of UM. Using UM patient samples, we identified that increased levels of CysLT1 in tumours is associated with reduced patient survival. Using UM cell lines and zebrafish models, we found that drugs targeting CysLT1, but not CysLT2, can alter hallmarks of cancer including cell growth, proliferation, and metabolism. This study is the first to examine the relationship of the CysLT receptors with clinical features of UM. Our data strengthen the importance of CysLT signalling in UM and suggest that antagonism of CysLT1 may be of therapeutic interest in the disease.
Metastatic uveal melanoma (UM) is a rare, but often lethal, form of ocular cancer arising from melanocytes within the uveal tract. UM has a high propensity to spread hematogenously to the liver, with up to 50% of patients developing liver metastases. Unfortunately, once liver metastasis occurs, patient prognosis is extremely poor with as few as 8% of patients surviving beyond two years. There are no standard-of-care therapies available for the treatment of metastatic UM, hence it is a clinical area of urgent unmet need. Here, the clinical relevance and therapeutic potential of cysteinyl leukotriene receptors (CysLT1 and CysLT2) in UM was evaluated. High expression of CYSLTR1 or CYSLTR2 transcripts is significantly associated with poor disease-free survival and poor overall survival in UM patients. Digital pathology analysis identified that high expression of CysLT1 in primary UM is associated with reduced disease-specific survival (p = 0.012; HR 2.76; 95% CI 1.21–6.3) and overall survival (p = 0.011; HR 1.46; 95% CI 0.67–3.17). High CysLT1 expression shows a statistically significant (p = 0.041) correlation with ciliary body involvement, a poor prognostic indicator in UM. Small molecule drugs targeting CysLT1 were vastly superior at exerting anti-cancer phenotypes in UM cell lines and zebrafish xenografts than drugs targeting CysLT2. Quininib, a selective CysLT1 antagonist, significantly inhibits survival (p < 0.0001), long-term proliferation (p < 0.0001), and oxidative phosphorylation (p < 0.001), but not glycolysis, in primary and metastatic UM cell lines. Quininib exerts opposing effects on the secretion of inflammatory markers in primary versus metastatic UM cell lines. Quininib significantly downregulated IL-2 and IL-6 in Mel285 cells (p < 0.05) but significantly upregulated IL-10, IL-1β, IL-2 (p < 0.0001), IL-13, IL-8 (p < 0.001), IL-12p70 and IL-6 (p < 0.05) in OMM2.5 cells. Finally, quininib significantly inhibits tumour growth in orthotopic zebrafish xenograft models of UM. These preclinical data suggest that antagonism of CysLT1, but not CysLT2, may be of therapeutic interest in the treatment of UM. View Full-Text
Keywords: uveal melanoma; cysteinyl leukotriene receptors; patient survival; G protein-coupled receptors; angiogenesis; inflammation; metabolism; zebrafish xenograft models uveal melanoma; cysteinyl leukotriene receptors; patient survival; G protein-coupled receptors; angiogenesis; inflammation; metabolism; zebrafish xenograft models
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Figure 1

MDPI and ACS Style

Slater, K.; Heeran, A.B.; Garcia-Mulero, S.; Kalirai, H.; Sanz-Pamplona, R.; Rahman, A.; Al-Attar, N.; Helmi, M.; O’Connell, F.; Bosch, R.; Portela, A.; Villanueva, A.; Gallagher, W.M.; Jensen, L.D.; Piulats, J.M.; Coupland, S.E.; O’Sullivan, J.; Kennedy, B.N. High Cysteinyl Leukotriene Receptor 1 Expression Correlates with Poor Survival of Uveal Melanoma Patients and Cognate Antagonist Drugs Modulate the Growth, Cancer Secretome, and Metabolism of Uveal Melanoma Cells. Cancers 2020, 12, 2950. https://doi.org/10.3390/cancers12102950

AMA Style

Slater K, Heeran AB, Garcia-Mulero S, Kalirai H, Sanz-Pamplona R, Rahman A, Al-Attar N, Helmi M, O’Connell F, Bosch R, Portela A, Villanueva A, Gallagher WM, Jensen LD, Piulats JM, Coupland SE, O’Sullivan J, Kennedy BN. High Cysteinyl Leukotriene Receptor 1 Expression Correlates with Poor Survival of Uveal Melanoma Patients and Cognate Antagonist Drugs Modulate the Growth, Cancer Secretome, and Metabolism of Uveal Melanoma Cells. Cancers. 2020; 12(10):2950. https://doi.org/10.3390/cancers12102950

Chicago/Turabian Style

Slater, Kayleigh, Aisling B. Heeran, Sandra Garcia-Mulero, Helen Kalirai, Rebeca Sanz-Pamplona, Arman Rahman, Nebras Al-Attar, Mays Helmi, Fiona O’Connell, Rosa Bosch, Anna Portela, Alberto Villanueva, William M. Gallagher, Lasse D. Jensen, Josep M. Piulats, Sarah E. Coupland, Jacintha O’Sullivan, and Breandán N. Kennedy 2020. "High Cysteinyl Leukotriene Receptor 1 Expression Correlates with Poor Survival of Uveal Melanoma Patients and Cognate Antagonist Drugs Modulate the Growth, Cancer Secretome, and Metabolism of Uveal Melanoma Cells" Cancers 12, no. 10: 2950. https://doi.org/10.3390/cancers12102950

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