Targeting the mesenchymal subtype in glioblastoma and other cancers via inhibition of diacylglycerol kinase alpha

Olmez, Inan; Love, Shawn; Xiao, Aizhen; Manigat, Laryssa; Randolph, Peyton; McKenna, Brian D.; Neal, Brian; Boroda, Salome; Li, Ming; Brenneman, Breanna; Abounader, Roger; Floyd, Desiree H.; Lee, Jeongwu; Nakano, ﻿Ichiro; Godlewski, Jakub; Bronisz, Agnieszka; Sulman, Erik P.; Mayo, Marty W.; Gioeli, Daniel; Weber, Michael J.; Harris, Thurl E.; Purow, Benjamin

doi:10.1093/neuonc/nox119

Cited by 51 publications

(51 citation statements)

References 33 publications

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“…Based on gene expression patterns and clinical characteristics, GBM has been classified into four subtypes: Proneural, neural, classical, and mesenchymal [6]. Among these subtypes, mesenchymal-type GBM exhibits the most aggressive phenotypes (e.g., TMZ resistance), and therefore, results in a worse prognosis in GBM patients [6,29]. Here, we show that H2AFJ differs from other H2A subfamily members in that it is highly expressed by mesenchymal-type GBM tissues and serves as a predictive factor for TMZ effectiveness in GBM patients.…”

Section: Discussionmentioning

confidence: 99%

Histone 2A Family Member J Drives Mesenchymal Transition and Temozolomide Resistance in Glioblastoma Multiforme

Lee

Lin

et al. 2019

Cancers

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Glioblastoma multiforme (GBM) is the most aggressive brain tumor and has a poor prognosis and is poorly sensitive to radiotherapy or temozolomide (TMZ) chemotherapy. Therefore, identifying new biomarkers to predict therapeutic responses of GBM is urgently needed. By using The Cancer Genome Atlas (TCGA) database, we found that the upregulation of histone 2A family member J (H2AFJ), but not other H2AFs, is extensively detected in the therapeutic-insensitive mesenchymal, IDH wildtype, MGMT unmethylated, or non-G-CIMP GBM and is associated with poor TMZ responsiveness independent of radiation. Similar views were also found in GBM cell lines. Whereas H2AFJ knockdown diminished TMZ resistance, H2AFJ overexpression promoted TMZ resistance in a panel of GBM cell lines. Gene set enrichment analysis (GSEA) revealed that H2AFJ upregulation accompanied by the activation of TNF-α/NF-κB and IL-6/STAT3-related pathways is highly predicted. Luciferase-based promoter activity assay further validated that the activities of NF-κB and STAT3 are causally affected by H2AFJ expression in GBM cells. Moreover, we found that therapeutic targeting HADC3 by tacedinaline or NF-κB by ML029 is likely able to overcome the TMZ resistance in GBM cells with H2AFJ upregulation. Significantly, the GBM cohorts harboring a high-level H2AFJ transcript combined with high-level expression of TNF-α/NF-κB geneset, IL-6/STAT3 geneset or HADC3 were associated with a shorter time to tumor repopulation after initial treatment with TMZ. These findings not only provide H2AFJ as a biomarker to predict TMZ therapeutic effectiveness but also suggest a new strategy to combat TMZ-insensitive GBM by targeting the interaction network constructed by TNF-α/NF-κB, IL-6/STAT3, HDAC3, and H2AFJ.

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Section: Discussionmentioning

confidence: 99%

Histone 2A Family Member J Drives Mesenchymal Transition and Temozolomide Resistance in Glioblastoma Multiforme

Lee

Lin

et al. 2019

Cancers

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“…The latest 2016 WHO classification of CNS tumours is a huge step forward as it significantly improves classification of gliomas by incorporating molecular data in a glioma diagnostics. However, discussions about previously described proneural and mesenchymal subtypes are still ongoing [13,14,15]. From all these subtypes, especially, mesenchymal subtype is one of the most consistent subtypes described in the literature [14,15,16].…”

Section: Discussionmentioning

confidence: 98%

“…However, discussions about previously described proneural and mesenchymal subtypes are still ongoing [13,14,15]. From all these subtypes, especially, mesenchymal subtype is one of the most consistent subtypes described in the literature [14,15,16]. Identification of mesenchymal signature in glioma tissues brings certain clinical interest because it is associated with worse prognosis [3,17].…”

Section: Discussionmentioning

confidence: 99%

Molecular classification of diffuse gliomas

Jakovlevs¹,

Vanags²,

Gardovskis³

et al. 2019

pjp

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In this study we assessed whether gliomas could be subdivided into different molecular subtypes by immunohistochemistry (IHC) reminiscent of those first described by Verhaak et al. in 2010 (classical, proneural, mesenchymal and neural). We also evaluated the prognostic significance of single molecular factors and searched for significant correlations between markers. In this study, we included 146 patients with glioblastomas (GBMs) and 26 with diffuse astrocytomas (DAs). The glioma samples were tested for PDGFRA, IDH1 R132H, CD44, p53, Ki-67, p21 and p27 expression. We found that gliomas could be subdivided into molecular subtypes by IHC. Fifty per cent of GBMs were of the proneural subtype, 18.5% of mesenchymal subtype and 31.5% were not otherwise classified. However, most of the DAs (92.3%) belonged to the proneural subtype. No prognostic role was found for the molecular subtypes, but predictive roles were noted. Both proneural and mesenchymal molecular subtypes showed a benefit from the addition of chemotherapy and radiotherapy; however, the mesenchymal subtype showed a greater response. Interestingly, the mesenchymal subtype did not receive any benefit from the addition of radiotherapy compared with palliative management and surgery alone. Regarding single molecular markers, only IDH1 R132H was found to have a prognostic role for GBMs. There was a trend towards better survival in tumours with lower PDGFRA expression (p = 0.066). In DAs, PDGFRA and Ki-67 expression had prognostic roles. The following statistically significant correlations were found in GBMs: Ki-67/p53, Ki-67/p27 and p53/PDGFRA; in DAs: p53/ PDGFRA, CD44/PDGFRA, and p21/PDGFRA.

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“…In this study, we set out to define the target spectrum of ritanserin to better understand its mode of action in tumor cells. Previous reports demonstrated that ritanserin is cytotoxic against glioblastoma and melanoma through putative downstream targets of DGKa, including mammalian target of rapamycin (Dominguez et al, 2013), hypoxia-inducible factor 1-a (Dominguez et al, 2013), and geranylgeranyl transferase I (Olmez et al, 2018). We hypothesize that ritanserin's cellular activity is mediated through blockade of kinase networks to explain its broad action against diverse tumor cell types.…”

Section: Introductionmentioning

confidence: 83%

Chemoproteomic Discovery of a Ritanserin-Targeted Kinase Network Mediating Apoptotic Cell Death of Lung Tumor Cells

et al. 2018

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Ritanserin was tested in the clinic as a serotonin receptor inverse agonist but recently emerged as a novel kinase inhibitor with potential applications in cancer. Here, we discovered that ritanserin induced apoptotic cell death of non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) cells via a serotonin-independent mechanism. We used quantitative chemical proteomics to reveal a ritanserin-dependent kinase network that includes key mediators of lipid [diacylglycerol kinase , phosphatidylinositol 4-kinase] and protein [feline encephalitis virus-related kinase, rapidly accelerated fibrosarcoma (RAF)] signaling, metabolism [eukaryotic elongation factor 2 kinase, eukaryotic translation initiation factor 2- kinase 4], and DNA damage response [tousled-like kinase 2] to broadly kill lung tumor cell types. Whereas ritanserin exhibited polypharmacology in NSCLC proteomes, this compound showed unexpected specificity for c-RAF in the SCLC subtype, with negligible activity against other kinases mediating mitogen-activated protein kinase signaling. Here we show that ritanserin blocks c-RAF but not B-RAF activation of established oncogenic signaling pathways in live cells, providing evidence in support of c-RAF as a key target mediating its anticancer activity. Given the role of c-RAF activation in RAS-mutated cancers resistant to clinical B-RAF inhibitors, our findings may have implications in overcoming resistance mechanisms associated with c-RAF biology. The unique target landscape combined with acceptable safety profiles in humans provides new opportunities for repositioning ritanserin in cancer.

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Targeting the mesenchymal subtype in glioblastoma and other cancers via inhibition of diacylglycerol kinase alpha

Abstract: Our findings demonstrate that a DGKα-GGTase I pathway can be targeted to combat the treatment-resistant mesenchymal cancer phenotype. Combining therapies with greater activity against each GBM subtype may represent a viable therapeutic option against GBM.

Cited by 51 publications

References 33 publications

Histone 2A Family Member J Drives Mesenchymal Transition and Temozolomide Resistance in Glioblastoma Multiforme

Histone 2A Family Member J Drives Mesenchymal Transition and Temozolomide Resistance in Glioblastoma Multiforme

Molecular classification of diffuse gliomas

Chemoproteomic Discovery of a Ritanserin-Targeted Kinase Network Mediating Apoptotic Cell Death of Lung Tumor Cells

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