Diacylglycerol Kinase alpha in X Linked Lymphoproliferative Disease Type 1

Velnati, Suresh; Centonze, Sara; Girivetto, Federico; Baldanzi, Gianluca

doi:10.3390/ijms22115816

Cited by 6 publications

(9 citation statements)

References 85 publications

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“…Furthermore, it was shown that ritanserin can synergise with irradiation and with imatinib, a tyrosine kinase inhibitor, to decrease cell proliferation of mesenchymal glioblastoma cells ( Olmez et al, 2018 ). Similarly, the DGKα-specific inhibitor Amb639752 promotes restimulated apoptosis of cells in vitro and in animal models of X-linked lymphoproliferative disease type 1, which have elevated DGKα activity ( Velnati et al, 2021a , b , 2020 ). These studies, along with our own findings, suggest that ritanserin as well as other DGKα inhibitors would be good candidates to be developed clinically as anti-cancer drugs and to be used in combination with trametinib or other EGFR-Ras pathway inhibitors, particularly in Ras-driven cancers.…”

Section: Discussionmentioning

confidence: 99%

A Drosophila chemical screen reveals synergistic effect of MEK and DGKα inhibition in Ras-driven cancer

Marca

Ely

Diepstraten

et al. 2023

Disease Models &Amp; Mechanisms

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Elevated RAS signalling is highly prevalent in human cancer, however targeting RAS-driven cancers with RAS-pathway inhibitors often leads to undesirable side-effects and to drug resistance. Thus, identifying compounds that synergise with RAS-pathway inhibitors would enable lower doses of the RAS-pathway inhibitors to be used and also decrease the acquisition of drug resistance. Here, in a boutique chemical screen using a Drosophila model of Ras-driven cancer, we have identified compounds that reduce tumour size by synergising with subtherapeutic doses of the Ras-pathway inhibitor, Trametinib. Analysis of one of the hits, Ritanserin, and related compounds revealed that diacyl glycerol kinase alpha (DGKa) was the critical target required for synergism with Trametinib. Human epithelial cells harbouring the H-RAS oncogene and knockdown of the cell polarity gene, SCRIB, are also sensitive to treatment with Trametinib and DGKa inhibitors. Mechanistically, DGKa inhibition synergises with Trametinib, by increasing the P38 stress-response signalling pathway in H-RAS SCRIB-RNAi cells, which could lead to cell quiescence. Our results reveal that targeting RAS-driven human cancers with RAS-pathway and DGKa inhibitors should be an effective combination drug therapy.

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Section: Discussionmentioning

confidence: 99%

A Drosophila chemical screen reveals synergistic effect of MEK and DGKα inhibition in Ras-driven cancer

Marca

Ely

Diepstraten

et al. 2023

Disease Models &Amp; Mechanisms

View full text Add to dashboard Cite

show abstract

“…Furthermore, it was shown that Ritanserin can synergize with irradiation and with Imatinib, a tyrosine kinase inhibitor, to decrease cell proliferation of mesenchymal glioblastoma cells (Olmez et al, 2018). Similarly, the DGK α -specific inhibitor, Amb639752, promotes restimulated apoptosis of cells in vitro and in animal models of X-linked lymphoproliferative disease type 1, which have elevated DGK α activity (Velnati et al, 2021a; Velnati et al, 2021b; Velnati et al, 2020). These studies, along with our own findings, suggests that Ritanserin, as well as other DGK α inhibitors, would be good candidates to be developed clinically as anti-cancer drugs and to be used in combination with Trametinib or other EGFR-RAS pathway inhibitors, particularly in Ras-driven cancers.…”

Section: Discussionmentioning

confidence: 99%

A Drosophila in vivo chemical screen reveals that combination drug treatment targeting MEK and DGKα mitigates Ras-driven polarity-impaired tumourigenesis

Richardson

Marca

Ely

et al. 2022

Preprint

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The RAS oncogene and upregulation of the RAS signalling pathway is highly prevalent in human cancer, and therefore, therapeutically targeting the RAS pathway is a common treatment in cancer. However, RAS pathway upregulation is not sufficient to drive malignant cancer, since senescence mechanisms prevent cancer progression. Thus, additional mutations, such as mutations that prevent senescence or alter the tissue architecture (cell polarity), are required for RAS-driven tumour progression. Moreover, targeting RAS-driven cancers with RAS pathway inhibitors can often lead to undesirable side-effects and to drug resistance. Thus, identifying compounds that synergise with RAS-pathway inhibitors would enable lower doses of the RAS pathway inhibitors to be used and also decrease the acquisition of drug resistance. Here, in a boutique chemical screen using a Drosophila model of Ras-driven cell polarity-impaired cancer, we have identified compounds that reduce tumour burden by synergising with subtherapeutic doses of the RAS pathway inhibitor, Trametinib, which inhibits mitogen-activated kinase kinase (MEK). Analysis of one of the hits from the screen, Ritanserin, which targets serotonin receptors and diacy glycerol kinase alpha (DGK&{alpha]), revealed that DGK&{alpha] was the critical target in its synergism with Trametinib. We show that human mammary epithelial cells harbouring the H-RAS oncogene and knockdown of the cell polarity gene, SCRIB, are also sensitive to treatment with low doses of Trametinib and DGK&{alpha] inhibition. Mechanistically, DGK&{alpha] inhibition synergises with Trametinib by inhibiting MEK and mTOR activity. Altogether, our results provide evidence that targeting RAS-driven human cancers with RAS pathway and DGK&{alpha] inhibitors will be an effective combination therapy.

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“…WASp presence inhibits DGKa enzymatic activity promoted by calcium, putatively impairing the shift to the active conformation for which the recoverin homology domain is required (31). SAP-deficient cells drives defective cytokine induction and RICD, which are rescued by the DGKa inhibition (14,15). Since a similar defect in RICD and IL-2 induction is present in murine WASp deficient cells (22, 33), we evaluated the effect of DGKa inhibition on RICD, TCR signalling potency, and IL-2 production in WASpdeficient human lymphocytes.…”

Section: Wasp Binds and Directly Inhibits Dgkamentioning

confidence: 99%

Wiskott-Aldrich syndrome protein interacts and inhibits diacylglycerol kinase alpha promoting IL-2 induction

et al. 2023

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BackgroundPhosphorylation of diacylglycerol by diacylglycerol-kinases represents a major inhibitory event constraining T cell activation upon antigen engagement. Efficient TCR signalling requires the inhibition of the alpha isoform of diacylglycerol kinase, DGKα, by an unidentified signalling pathway triggered by the protein adaptor SAP. We previously demonstrated that, in SAP absence, excessive DGKα activity makes the T cells resistant to restimulation-induced cell death (RICD), an apoptotic program counteracting excessive T cell clonal expansion.ResultsHerein, we report that the Wiskott-Aldrich syndrome protein (WASp) inhibits DGKα through a specific interaction of the DGKα recoverin homology domain with the WH1 domain of WASp. Indeed, WASp is necessary and sufficient for DGKα inhibition, and this WASp function is independent of ARP2/3 activity. The adaptor protein NCK-1 and the small G protein CDC42 connect WASp-mediated DGKα inhibition to SAP and the TCR signalosome. In primary human T cells, this new signalling pathway is necessary for a full response in terms of IL-2 production, while minimally affecting TCR signalling and restimulation-induced cell death. Conversely, in T cells made resistant to RICD by SAP silencing, the enhanced DAG signalling due to DGKα inhibition is sufficient to restore apoptosis sensitivity.ConclusionWe discover a novel signalling pathway where, upon strong TCR activation, the complex between WASp and DGKα blocks DGKα activity, allowing a full cytokine response.

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Diacylglycerol Kinase alpha in X Linked Lymphoproliferative Disease Type 1

Cited by 6 publications

References 85 publications

A Drosophila chemical screen reveals synergistic effect of MEK and DGKα inhibition in Ras-driven cancer

A Drosophila chemical screen reveals synergistic effect of MEK and DGKα inhibition in Ras-driven cancer

A Drosophila in vivo chemical screen reveals that combination drug treatment targeting MEK and DGKα mitigates Ras-driven polarity-impaired tumourigenesis

Wiskott-Aldrich syndrome protein interacts and inhibits diacylglycerol kinase alpha promoting IL-2 induction

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