Uveal Melanoma Oncogene<i>CYSLTR2</i>Encodes a Constitutively Active GPCR Highly Biased Toward Gq Signaling

Ceraudo, Emilie; Horioka, Mizuho; Jm, Mattheisen; Hitchman, Tyler D.; Moore, A Russell; Ma, Kazmi; Chi, Ping; Chen, Y; Sakmar, Thomas P.; Huber, Thomas

doi:10.1101/663153

Cited by 13 publications

(12 citation statements)

References 70 publications

(56 reference statements)

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“…qPCR and western blot analysis confirmed equivalent expression of both receptors in Mel285 and OMM2.5 cell lines suggesting that phenotypic differences observed following drug treatment are not due to differences in CysLT receptor expression. The CysLT 2 antagonist HAMI 3379 was previously tested in Leu129Gln CysLT 2 UM oncogene models but showed limited activity as an inverse agonist in these models of constitutive CysLT 2 activation [ 54 ]. To our knowledge, no previous studies have investigated the anti-cancer potential of CysLT 1 antagonists in UM.…”

Section: Discussionmentioning

confidence: 99%

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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Heeran

García-Mulero

et al. 2020

Cancers

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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.

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Section: Discussionmentioning

confidence: 99%

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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Heeran

García-Mulero

et al. 2020

Cancers

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“…Constitutive activation of the receptor (as seen with the p.L129Q mutation) leads to oncogenic signalling, cell proliferation and enforcement of a melanocyte-lineage-specific transcriptional program in vitro and in vivo (9,10). Similarly, associations with a heavily pigmented phenotype have been reported in other melanocytic neoplasms carrying the p.L129Q mutation (30).…”

Section: Discussionmentioning

confidence: 88%

“…The essential role of Gα q signalling in uveal melanoma tumorigenesis has been further supported by the discovery of rare but recurrent mutations in PLCB4 (p.D630) and CYSLTR2 (p.L129Q) (8,9). These genes, encoding phospholipase C β 4 and a Gα q -coupled receptor respectively, are typically mutated in GNAQ and GNA11 wild-type tumours, providing an alternative way of activating the Gα q signalling pathway (10,11).…”

Section: Introductionmentioning

confidence: 99%

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Involvement of mutant and wild-type CYSLTR2 in the development and progression of uveal nevi and melanoma

Nell

Menger

Versluis

et al. 2020

Preprint

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Background Activating Gαq signalling mutations are considered an early event in the development of uveal melanoma. Whereas most tumours harbour a mutation in GNAQ or GNA11, CYSLTR2 (encoding G-protein coupled receptor CysLT2R) forms a rare alternative. The role of wild-type CysLT2R in uveal melanoma remains unknown. Methods We performed a digital PCR-based molecular analysis of benign choroidal nevi and primary uveal melanomas. Publicly available bulk and single cell sequencing data were mined to further study wild-type and mutant CYSLTR2. Results 1/16 nevi and 2/120 melanomas carried the CYSLTR2 mutation. The mutation was subclonal in the nevus, while being clonal in both melanomas. In the melanomas, secondary, subclonal CYSLTR2 alterations shifted the allelic balance towards the mutant. The resulting genetic heterogeneity was confirmed in distinct areas of both tumours. At the RNA level, further silencing of wild-type and preferential expression of mutant CYSLTR2 was identified, which was also observed in 2/3 CYSLTR2 mutant melanomas from the TCGA cohort. In CYSLTR2 wild-type melanomas, high expression of CYSLTR2 originated from melanoma cells and correlated to tumour inflammation. Conclusions Our findings suggest that CYSLTR2 is involved in both early and late development of uveal melanoma. Whereas the CYSLTR2 p.L129Q mutation is likely to be the initiating oncogenic event, various mechanisms further increase the mutant allele abundance during tumour progression. This makes mutant CysLT2R an attractive therapeutic target in uveal melanoma. In GNAQ, GNA11 and PLCB4 mutant melanomas, expression of wild-type CYSLTR2 possibly facilitates an interaction with immune cells in the microenvironment and may also have therapeutic potential.

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“…Aside from mutationally activated G␣ subunits, an additional recurrent hotspot mutation in UM was recently identified in the CYSLTR2 gene, which codes for the G proteincoupled cysteinyl-leukotriene receptor type 2: CysLTR2 L129Q (77). A hallmark feature of this mutant receptor is an overactive G q signaling cascade coupled with impaired arrestin-mediated down-regulation, abolished responsiveness to its cognate endogenous ligands, and insensitivity to CysLTR2 antagonist/ inverse agonist ligands (78). It follows that inhibitors of G q function such as FR or YM should have therapeutic potential to suppress the aberrant activity of this signaling module originating on either the receptor or the G protein level.…”

Section: When the Balance Is Tipped Toward The On Statementioning

confidence: 99%

Heterotrimeric Gq proteins as therapeutic targets?

Kostenis¹,

Pfeil²,

Annala³

2020

Journal of Biological Chemistry

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Heterotrimeric G proteins are the core upstream elements that transduce and amplify the cellular signals from G protein–coupled receptors (GPCRs) to intracellular effectors. GPCRs are the largest family of membrane proteins encoded in the human genome and are the targets of about one-third of prescription medicines. However, to date, no single therapeutic agent exerts its effects via perturbing heterotrimeric G protein function, despite a plethora of evidence linking G protein malfunction to human disease. Several recent studies have brought to light that the Gq family–specific inhibitor FR900359 (FR) is unexpectedly efficacious in silencing the signaling of Gq oncoproteins, mutant Gq variants that mostly exist in the active state. These data not only raise the hope that researchers working in drug discovery may be able to potentially strike Gq oncoproteins from the list of undruggable targets, but also raise questions as to how FR achieves its therapeutic effect. Here, we place emphasis on these recent studies and explain why they expand our pharmacological armamentarium for targeting Gq protein oncogenes as well as broaden our mechanistic understanding of Gq protein oncogene function. We also highlight how this novel insight impacts the significance and utility of using G(q) proteins as targets in drug discovery efforts.

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Uveal Melanoma OncogeneCYSLTR2Encodes a Constitutively Active GPCR Highly Biased Toward Gq Signaling

Cited by 13 publications

References 70 publications

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

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

Involvement of mutant and wild-type CYSLTR2 in the development and progression of uveal nevi and melanoma

Heterotrimeric Gq proteins as therapeutic targets?

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