The RAS-BRAF kinase pathway is not involved in uveal melanoma

Kılıç, Emine; Ht, Brüggenwirth; Mm, Verbiest; Ec, Zwarthoff; Nm, Mooy; Gp, Luyten; A, de Klein

doi:10.1097/01.cmr.0000130006.46885.a0

Cited by 44 publications

(9 citation statements)

References 11 publications

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“…Sequencing analysis confirmed that GNAQ is wild type in cell lines C918, Ocm1, Ocm3 and Mel285, while codon 209 of GNAQ is mutated from CAA (glutamine) to CTA (leucine) in cell lines Mel202 and 92.1 and to CCA (proline) in cell line Omm1.3. Cell lines Ocm1 and Ocm3 have BRAF V600E mutation (19, 20). AEB071 at low micromolar concentrations significantly decreased viability of all three GNAQ mutated cell lines (Figure 1C).…”

Section: Resultsmentioning

confidence: 99%

“…Other pathways presumably regulate NF-κB activation in GNAQ wild type cells. For example, Ocm1 and Ocm3 cells have been shown to carry the common V600E BRAF mutation that constitutively activates the MAPK and NF-κB pathways (19, 20, 44–46). High c-Met expression has been found in C918 and Mel285 cells (47) and it has been reported that NF-κB can be activated by HGF/c-Met signaling (48, 49).…”

Section: Discussionmentioning

confidence: 99%

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Protein Kinase C Inhibitor AEB071 Targets Ocular Melanoma Harboring GNAQ Mutations via Effects on the PKC/Erk1/2 and PKC/NF-κB Pathways

Zhu

et al. 2012

Molecular Cancer Therapeutics

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Somatic GNAQ mutations at codon 209 have been identified in approximately 50% of uveal melanomas (UM) and have been reported to be oncogenic through activating PLCβ-PKC-Erk1/2 pathways. We hypothesized that PKC may provide new opportunities for therapeutic targeting of UM carrying GNAQ mutations. To test this hypothesis, UM cells harboring wild type or mutant GNAQ were treated with the PKC inhibitor AEB071 (sotrastaurin) or infected with lentivirus expressing shRNAs targeting PKC isoforms. Notably, AEB071 at low micromolar concentrations significantly inhibited the growth of UM cells harboring GNAQ mutations through induction of G1 arrest and apoptosis. However, AEB071 had little effect on UM cells carrying wild type GNAQ. AEB071-mediated cell inhibition in the GNAQ mutated UM was accompanied by inhibition of Erk1/2 phosphorylation, NF-κB, decreased expression of cyclin D1, survivin, Bcl-xL and XIAP, and increased expression of cyclin-dependent kinase inhibitor p27Kip1. AEB071 suppressed the expression of PKC α, β, δ, ε and θ in GNAQ mutated UM cells. Our findings from shRNA-mediated knockdown studies revealed that these PKC isoforms are functionally important for UM cells harboring GNAQ mutations. Furthermore, inhibitors of Erk1/2 and NF-κB pathways reduced viability of UM cells. Together, our findings demonstrate that AEB071 exerts antitumor action on UM cells carrying GNAQ mutations via targeting PKC/Erk1/2 and PKC/NF-κB pathways. Targeted PKC inhibition with drugs such as AEB071 offers novel therapeutic potential for UM harboring GNAQ mutations.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Protein Kinase C Inhibitor AEB071 Targets Ocular Melanoma Harboring GNAQ Mutations via Effects on the PKC/Erk1/2 and PKC/NF-κB Pathways

Zhu

et al. 2012

Molecular Cancer Therapeutics

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“…However, enzastaurin did not significantly alter Erk1/2 phosphorylation in both cell lines, suggesting other PKC isoforms and/or PKC independent mechanisms for Erk1/2 activation in Ocm1 cells. Complicating this interpretation, Ocm1 cells have been shown to carry the common V600E BRAF mutation that constitutively activates the MAPK pathway [43], [44]. Furthermore, PKCα and PKCδ have been reported to activate Erk1/2 in mouse melanoma [51].…”

Section: Discussionmentioning

confidence: 95%

The Protein Kinase C Inhibitor Enzastaurin Exhibits Antitumor Activity against Uveal Melanoma

Zhu

Fletcher

et al. 2012

PLoS ONE

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GNAQ mutations at codon 209 have been recently identified in approximately 50% of uveal melanomas (UM) and are reported to be oncogenic through activating the MAPK/Erk1/2 pathway. Protein kinase C (PKC) is a component of signaling from GNAQ to Erk1/2. Inhibition of PKC might regulate GNAQ mutation-induced Erk1/2 activation, resulting in growth inhibition of UM cells carrying GNAQ mutations. UM cells carrying wild type or mutant GNAQ were treated with the PKC inhibitor enzastaurin. Effects on proliferation, apoptosis, and signaling events were evaluated. Enzastaurin downregulated the expression of several PKC isoforms including PKCβII PKCθ, PKCε and/or their phosphorylation in GNAQ mutated cells. Downregulation of these PKC isoforms in GNAQ mutated cells by shRNA resulted in reduced viability. Enzastaurin exhibited greater antiproliferative effect on GNAQ mutant cells than wild type cells through induction of G1 arrest and apoptosis. Enzastaurin-induced G1 arrest was associated with inhibition of Erk1/2 phosphorylation, downregulation of cyclin D1, and accumulation of cyclin dependent kinase inhibitor p27Kip1. Furthermore, enzastaurin reduced the expression of antiapoptotic Bcl-2 and survivin in GNAQ mutant cells. Inhibition of Erk1/2 phosphorylation with a MEK specific inhibitor enhanced the sensitivity of GNAQ wild type cells to enzastaurin, accompanied by p27Kip1 accumulation and/or inhibition of enzastaurin-induced survivin and Bcl-2 upregulation. PKC inhibitors such as enzastaurin have activity against UM cells carrying GNAQ mutations through inhibition of the PKC/Erk1/2 pathway and induction of G1 arrest and apoptosis. Inhibition of the PKC pathway provides a basis for clinical investigation in patients with UM.

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“…Ocular MM comprise about 3% of all MM and mucosal MM about 1% and patients with these subgroups have in general a worse OS than patients diagnosed with cutaneous MM [ 17 ]. In addition, mucosal MMs do only have a mutated BRAF gene in 6% of cases [ 18 ] while uveal MMs are not mutated [ 19 ]. Hence, the need for better treatments is especially pronounced for these two subgroups.…”

Section: Discussionmentioning

confidence: 99%

Local irradiation does not enhance the effect of immunostimulatory AdCD40L gene therapy combined with low dose cyclophosphamide in melanoma patients

et al. 2017

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BackgroundAdCD40L is an immunostimulatory gene therapy under evaluation for advanced melanoma, including ocular melanoma. Herein, we present the final data of a Phase I/IIa trial using AdCD40L alone or in combination with low dose cyclophosphamide +/- radiation therapy.MethodsAdCD40L is a replication-deficient adenovirus carrying the gene for CD40 ligand (CD40L). Twenty-four patients with advanced melanoma were enrolled and treated with AdCD40L monotherapy, or combined with cyclophosphamide +/- single fraction radiotherapy. The patients were monitored for 10 weeks using immunological and radiological evaluations and thereafter for survival.ResultsAdCD40L treatment was safe and well tolerated both alone and in combination with cyclophosphamide as well as local radiotherapy. Four out of twenty-four patients had >1 year survival. Addition of cyclophosphamide was beneficial but adding radiotherapy did not further extend survival. High initial plasma levels of IL12 and MIP3b correlated to overall survival, whereas IL8 responses post-treatment correlated negatively with survival. Interestingly, antibody reactions to the virus correlated negatively with post IL6 and pre IL1b levels in blood.ConclusionsAdCD40L was safely administered to patients and effect was improved by cyclophosphamide but not by radiotherapy. Immune activation profile at baseline may predict responders better than shortly after treatment.

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The RAS-BRAF kinase pathway is not involved in uveal melanoma

Cited by 44 publications

References 11 publications

Protein Kinase C Inhibitor AEB071 Targets Ocular Melanoma Harboring GNAQ Mutations via Effects on the PKC/Erk1/2 and PKC/NF-κB Pathways

Protein Kinase C Inhibitor AEB071 Targets Ocular Melanoma Harboring GNAQ Mutations via Effects on the PKC/Erk1/2 and PKC/NF-κB Pathways

The Protein Kinase C Inhibitor Enzastaurin Exhibits Antitumor Activity against Uveal Melanoma

Local irradiation does not enhance the effect of immunostimulatory AdCD40L gene therapy combined with low dose cyclophosphamide in melanoma patients

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