AUTHOR=Slater Kayleigh , Bosch Rosa , Smith Kaelin Francis , Jahangir Chowdhury Arif , Garcia-Mulero Sandra , Rahman Arman , O’Connell Fiona , Piulats Josep M. , O’Neill Valerie , Horgan Noel , Coupland Sarah E. , O’Sullivan Jacintha , Gallagher William M. , Villanueva Alberto , Kennedy Breandán N. 

TITLE=1,4-dihydroxy quininib modulates the secretome of uveal melanoma tumour explants and a marker of oxidative phosphorylation in a metastatic xenograft model

JOURNAL=Frontiers in Medicine

VOLUME=9

YEAR=2023

URL=https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2022.1036322

DOI=10.3389/fmed.2022.1036322

ISSN=2296-858X

ABSTRACT=<p>Uveal melanoma (UM) is an intraocular cancer with propensity for liver metastases. The median overall survival (OS) for metastatic UM (MUM) is 1.07 years, with a reported range of 0.84–1.34. In primary UM, high cysteinyl leukotriene receptor 1 (CysLT<sub>1</sub>) expression associates with poor outcomes. CysLT<sub>1</sub> antagonists, quininib and 1,4-dihydroxy quininib, alter cancer hallmarks of primary and metastatic UM cell lines <italic>in vitro</italic>. Here, the clinical relevance of CysLT receptors and therapeutic potential of quininib analogs is elaborated in UM using preclinical <italic>in vivo</italic> orthotopic xenograft models and <italic>ex vivo</italic> patient samples. Immunohistochemical staining of an independent cohort (<italic>n</italic> = 64) of primary UM patients confirmed high CysLT<sub>1</sub> expression significantly associates with death from metastatic disease (<italic>p</italic> = 0.02; HR 2.28; 95% CI 1.08–4.78), solidifying the disease relevance of CysLT<sub>1</sub> in UM. In primary UM samples (<italic>n</italic> = 11) cultured as <italic>ex vivo</italic> explants, 1,4-dihydroxy quininib significantly alters the secretion of IL-13, IL-2, and TNF-α. In an orthotopic, cell line-derived xenograft model of MUM, 1,4-dihydroxy quininib administered intraperitoneally at 25 mg/kg significantly decreases ATP5B expression (<italic>p</italic> = 0.03), a marker of oxidative phosphorylation. In UM, high <italic>ATP5F1B</italic> is a poor prognostic indicator, whereas low <italic>ATP5F1B</italic>, in combination with disomy 3, correlates with an absence of metastatic disease in the TCGA-UM dataset. These preclinical data highlight the diagnostic potential of CysLT<sub>1</sub> and <italic>ATP5F1B</italic> in UM, and the therapeutic potential of 1,4-dihydroxy quininib with <italic>ATP5F1B</italic> as a companion diagnostic to treat MUM.</p>