Combination therapy for hepatocellular carcinoma with diacylglycerol kinase alpha inhibition and anti-programmed cell death-1 ligand blockade

Okada, Naoki; Sugiyama, Ko; Shichi, Shunsuke; Shirai, Yasuhito; Goto, Kaoru; Sakane, Fumio; Kitamura, Hiroyuki; Taketomi, Akinobu

doi:10.1007/s00262-021-03041-z

Cited by 10 publications

(29 citation statements)

References 49 publications

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“…Elevated levels of DAG promotes colony-stimulating factor 1-dependent proliferation in DGK knock-out mice and modulates β-catenin/cyclinD1 levels in osteoclast precursors (67). DAG has also been associated with HCC progression (68,69). DAG, by either DGK-mediated phosphorylation into phosphatidic acid or activating protein kinase C, supports tumor growth and HCC progression (69)(70)(71).…”

Section: Discussionmentioning

confidence: 99%

Comparative membrane lipidomics of hepatocellular carcinoma cells reveals diacylglycerol and ceramide as key regulators of Wnt/β-catenin signaling and tumor growth

Azbazdar

Demırcı

Heger

et al. 2022

Preprint

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Hepatocellular carcinoma (HCC) is largely associated with aberrant activation of Wnt/β-catenin signaling. Nevertheless, how membrane lipid composition is altered in HCC cells with abnormal Wnt signaling remains elusive. Here, by exploiting comprehensive lipidome profiling, we unravel membrane lipid composition of six different HCC cell lines with mutations in components of Wnt/β-catenin signaling, leading to differences in their endogenous signaling activity. Among the differentially regulated lipids are diacylglycerol (DAG) and ceramide, which were downregulated at the membrane of HCC cells after Wnt3a stimulation. DAG and ceramide enhanced Wnt/β-catenin signaling in SNU475 and HepG2 cells. In contrast, depletion of DAG and ceramide suppressed Wnt/β-catenin signaling and significantly impeded the proliferation, tumor growth and in vivo migration capacity of SNU475 and HepG2 cells. This study, by pioneering plasma membrane lipidome profiling in HCC cells, exhibits the remarkable potential of lipids to correct dysregulated signaling pathways in cancer and stop abnormal tumor growth.

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Section: Discussionmentioning

confidence: 99%

Comparative membrane lipidomics of hepatocellular carcinoma cells reveals diacylglycerol and ceramide as key regulators of Wnt/β-catenin signaling and tumor growth

Azbazdar

Demırcı

Heger

et al. 2022

Preprint

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“…Compound A also induced apoptosis of several cancer-derived cells and simultaneously activated T cells [31]. The DGKα-selective inhibitor DGKAI, which was obtained along with compound A (see above), also selectively inhibited DGKα, DGKβ and DGKγ with IC 50 values of 0.01, 0.01, and <0.01 µM, respectively [90]. However, the IC 50 values for the other seven DGK isozymes were greater than 10 µM.…”

Section: Dgkα Inhibitors Simultaneously Attenuate Cancer Cell Proliferation and Activate T Cell Functionmentioning

confidence: 95%

“…However, the IC 50 values for the other seven DGK isozymes were greater than 10 µM. DGKAI was suggested to have dual effects on HCC proliferation (inhibition) and T cell immune response (activation) in vivo [90] (Figure 3). Unfortunately, structural information on these compounds is not currently available.…”

Section: Dgkα Inhibitors Simultaneously Attenuate Cancer Cell Proliferation and Activate T Cell Functionmentioning

confidence: 99%

“…Moreover, Arranz-Nicolas et al also showed the involvement of DGKα in CD3/CD28 and PD-1-Cancers 2021, 13, 5190 9 of 13 mediated signal transduction pathways and the ability of DGKα inhibitors (R59949 and ritanserin) to cooperatively enhance immune checkpoint-targeted therapies in human T lymphocytes [99,100]. Furthermore, Okada et al demonstrated that DGKα inhibition using DGKAI (see Section 5.1) and PD-L1 blockade synergistically suppressed the growth of HCC in vivo in an immune activity-dependent manner [90]. Therefore, the synergistic effect of DGKα inhibition and PD-1/PD-L1 blockade provides a promising strategy to strengthen the efficacy of immunotherapy in the treatment of cancer (Figure 3).…”

Section: Synergistic Effect Of Pd-1/pd-l1 Blockadementioning

confidence: 99%

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The Roles of Diacylglycerol Kinase α in Cancer Cell Proliferation and Apoptosis

Sakane

Hoshino

Ebina

et al. 2021

Cancers

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Diacylglycerol (DG) kinase (DGK) phosphorylates DG to generate phosphatidic acid (PA). The α isozyme is activated by Ca2+ through its EF-hand motifs and tyrosine phosphorylation. DGKα is highly expressed in several refractory cancer cells including melanoma, hepatocellular carcinoma, and glioblastoma cells. In melanoma cells, DGKα is an antiapoptotic factor that activates nuclear factor-κB (NF-κB) through the atypical protein kinase C (PKC) ζ-mediated phosphorylation of NF-κB. DGKα acts as an enhancer of proliferative activity through the Raf–MEK–ERK pathway and consequently exacerbates hepatocellular carcinoma progression. In glioblastoma and melanoma cells, DGKα attenuates apoptosis by enhancing the phosphodiesterase (PDE)-4A1–mammalian target of the rapamycin pathway. As PA activates PKCζ, Raf, and PDE, it is likely that PA generated by DGKα plays an important role in the proliferation/antiapoptosis of cancer cells. In addition to cancer cells, DGKα is highly abundant in T cells and induces a nonresponsive state (anergy), which represents the main mechanism by which advanced cancers escape immune action. In T cells, DGKα attenuates the activity of Ras-guanyl nucleotide-releasing protein, which is activated by DG and avoids anergy through DG consumption. Therefore, a DGKα-specific inhibitor is expected to be a dual effective anticancer treatment that inhibits cancer cell proliferation and simultaneously enhances T cell functions. Moreover, the inhibition of DGKα synergistically enhances the anticancer effects of programmed cell death-1/programmed cell death ligand 1 blockade. Taken together, DGKα inhibition provides a promising new treatment strategy for refractory cancers.

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“…DGKα inhibition has already been shown to boost the anti-cancer activity of CAR-T cells in preclinical studies [ 58 ], and other studies described above suggest its potential to promote NK cell- or macrophage-based immunotherapies as well. A recent report indicates anti-cancer synergy with the combination of DGKα inhibition and anti-PD1 checkpoint inhibitor activity, and this regimen may also have promise for GBM [ 59 ]. Though initial studies of anti-PD1 antibodies in patients with GBM were disappointing, there have been signs of activity in small studies of neoadjuvant anti-PD1 [ 60 , 61 ]; boosting T cell activity further with the addition of DGKα inhibition to neoadjuvant anti-PD1 may thus warrant testing for GBM.…”

Section: Likely Need For Combination Regimens With Dgkα Inhibition Ag...mentioning

confidence: 99%

Delivering Glioblastoma a Kick—DGKα Inhibition as a Promising Therapeutic Strategy for GBM

Purow

2022

Cancers

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Diacylglycerol kinase α (DGKα) inhibition may be particularly relevant for the treatment of glioblastoma (GBM), a relatively common brain malignancy incurable with current therapies. Prior reports have shown that DGKα inhibition has multiple direct activities against GBM cells, including suppressing the oncogenic pathways mTOR and HIF-1α. It also inhibits pathways associated with the normally treatment-resistant mesenchymal phenotype, yielding preferential activity against mesenchymal GBM; this suggests possible utility in combining DGKα inhibition with radiation and other therapies for which the mesenchymal phenotype promotes resistance. The potential for DGKα inhibition to block or reverse T cell anergy also suggests the potential of DGKα inhibition to boost immunotherapy against GBM, which is generally considered an immunologically “cold” tumor. A recent report indicates that DGKα deficiency increases responsiveness of macrophages, indicating that DGKα inhibition could also have the potential to boost macrophage and microglia activity against GBM—which could be a particularly promising approach given the heavy infiltration of these cells in GBM. DGKα inhibition may therefore offer a promising multi-pronged attack on GBM, with multiple direct anti-GBM activities and also the ability to boost both adaptive and innate immune responses against GBM. However, both the direct and indirect benefits of DGKα inhibition for GBM will likely require combinations with other therapies to achieve meaningful efficacy. Furthermore, GBM offers other challenges for the application of DGKα inhibitors, including decreased accessibility from the blood-brain barrier (BBB). The ideal DGKα inhibitor for GBM will combine potency, specificity, and BBB penetrability. No existing inhibitor is known to meet all these criteria, but the strong potential of DGKα inhibition against this lethal brain cancer should help drive development and testing of agents to bring this promising strategy to the clinic for patients with GBM.

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Combination therapy for hepatocellular carcinoma with diacylglycerol kinase alpha inhibition and anti-programmed cell death-1 ligand blockade

Cited by 10 publications

References 49 publications

Comparative membrane lipidomics of hepatocellular carcinoma cells reveals diacylglycerol and ceramide as key regulators of Wnt/β-catenin signaling and tumor growth

Comparative membrane lipidomics of hepatocellular carcinoma cells reveals diacylglycerol and ceramide as key regulators of Wnt/β-catenin signaling and tumor growth

The Roles of Diacylglycerol Kinase α in Cancer Cell Proliferation and Apoptosis

Delivering Glioblastoma a Kick—DGKα Inhibition as a Promising Therapeutic Strategy for GBM

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