PIK3CB/p110β is a selective survival factor for glioblastoma

Pridham, Kevin J.; Le, Lamvy; Guo, Sujuan; Varghese, Robin; Algino, Sarah Elizabeth; Liang, Yen Nan; Fajardin, Renee; Rodgers, Cara M.; Simonds, Gary R.; Kelly, Deborah F.; Sheng, Zhi

doi:10.1093/neuonc/nox181

Cited by 45 publications

(110 citation statements)

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“…Aberrant activation of the PI3K signaling pathway is found in nearly all isocitrate dehydrogenase (IDH) wild‐type glioblastomas, highlighting its importance as a therapeutic target. Mechanisms for PI3K/mTOR pathway activation include loss of tumor suppressor phosphatase and tensin homolog on chromosome ten (PTEN) function, activating mutations in phosphatidylinositol‐4,5‐bisphosphate 3‐kinase catalytic subunit alpha ( PIK3CA) , the gene encoding the catalytic subunit p110 alpha (p110α), and in phosphoinositide‐3‐kinase regulatory subunit 1 ( PIK3R1) , encoding the p85α regulatory subunit, or activation of growth factor receptor signaling, including epidermal growth factor receptor (EGFR) (Brennan et al ; Pridham et al ). Overexpression of PI3K p110 catalytic or p85 regulatory subunits of class I PI3K has been associated with invasiveness in glioblastoma (Luk et al ).…”

Section: Introductionmentioning

confidence: 99%

Synergistic growth inhibition mediated by dual PI3K/mTOR pathway targeting and genetic or direct pharmacological AKT inhibition in human glioblastoma models

Achenbach

Weller

Kaulich

et al. 2020

Journal of Neurochemistry

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Molecular genetic aberrations in the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway are common in human cancers including glioblastoma, yet, novel therapeutic approaches targeting this pathway in glioblastoma have not been successful. We hypothesized that molecular profiling in combination with in vitro drug sensitivity testing allows to identify signatures associated with sensitivity or resistance to PI3K/mTOR pathway inhibition. We analyzed the molecular mechanisms determining sensitivity to PI3K/mTOR inhibition using gene silencing or pharmacological target inhibition and proliferation, clonogenicity, or spherogenicity as readouts, in human long-term glioma cell (LTC) lines and glioma-initiating cells (GIC). Cultured glioma cells were universally sensitive to growth inhibition induced by PQR309, a novel, dual pan-PI3K/mTOR antagonist. Cells exhibited profound growth arrest, but little apoptotic or necrotic cell death as confirmed by electron microscopy; yet, there was evidence of senescence. Cell lines with high basal levels of phosphorylated (active) AKT, low levels of phosphorylated (inactive) protein translation repressor eukaryotic initiation factor (eIF) 4E-binding protein 1 (p4E-BP1), and high levels of Ser9-phosphorylated (inactive) glycogen synthase kinase 3 beta (pGSK3b) were more sensitive to PQR309. Accordingly, the activity of PQR309 was synergistically enhanced by AKT gene silencing or direct pharmacological AKT inhibition. In vivo studies confirmed the anti-glioma activity of PQR309 alone or in combination with AKT inhibition in the orthotopic LN-229 glioma xenograft model in nude mice. These data justify to explore combined targeted therapy approaches in glioblastoma that aim at down-regulating AKT function to enhance the therapeutic potential of dual PI3K/mTOR inhibitors.

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Section: Introductionmentioning

confidence: 99%

Synergistic growth inhibition mediated by dual PI3K/mTOR pathway targeting and genetic or direct pharmacological AKT inhibition in human glioblastoma models

Achenbach

Weller

Kaulich

et al. 2020

Journal of Neurochemistry

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“…Gene expression analysis was described previously with modifications 5 , 50 . The expression data of CK1 genes were retrieved from CellMiner, Oncomine, and The Human Protein Atlas.…”

Section: Methodsmentioning

confidence: 99%

“…shRNA-mediated knockdown was performed as previously described 50 , 51 . shRNAs of CK1ε and MELK (maternal embryonic leucine zipper kinase) were purchased from Thermo Fisher Scientific Inc.…”

Section: Methodsmentioning

confidence: 99%

“…Immunoblotting was performed as described in our previous reports 5 , 18 , 30 , 50 , 52 . In brief, cells were lysed and total protein was quantified using the Bradford assay (Bio-Rad Laboratories Inc.).…”

Section: Methodsmentioning

confidence: 99%

“…The MTS viability assay was described previously 18 , 50 , 52 . In brief, 1,000 to 2,000 cells were plated in a 96-well plate.…”

Section: Methodsmentioning

confidence: 99%

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Casein Kinase 1 Epsilon Regulates Glioblastoma Cell Survival

Varghese

Young

Pham

et al. 2018

Sci Rep

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Glioblastoma is the most common malignant brain cancer with a dismal prognosis. The difficulty in treating glioblastoma is largely attributed to the lack of effective therapeutic targets. In our previous work, we identified casein kinase 1 ε (CK1ε, also known as CSNK1E) as a potential survival factor in glioblastoma. However, how CK1ε controls cell survival remains elusive and whether targeting CK1ε is a possible treatment for glioblastoma requires further investigation. Here we report that CK1ε was expressed at the highest level among six CK1 isoforms in glioblastoma and enriched in high-grade glioma, but not glia cells. Depletion of CK1ε remarkably inhibited the growth of glioblastoma cells and suppressed self-renewal of glioblastoma stem cells, while having limited effect on astrocytes. CK1ε deprivation activated β-catenin and induced apoptosis, which was further counteracted by knockdown of β-catenin. The CK1ε inhibitor IC261, but not PF-4800567, activated β-catenin and blocked the growth of glioblastoma cells and glioblastoma stem cells. Congruently, IC261 elicited a robust growth inhibition of human glioblastoma xenografts in mice. Together, our results demonstrate that CK1ε regulates the survival of glioblastoma cells and glioblastoma stem cells through β-catenin signaling, underscoring the importance of targeting CK1ε as an effective treatment for glioblastoma.

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Mutational characteristics determined using circulating tumor DNA analysis in triple‐negative breast cancer patients with distant metastasis

Rong

et al. 2020

Cancer Communications

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Dear editor, Breast cancer has been considered as the most common malignancy and the leading cause of death in women worldwide [1]. Triple-negative breast cancer (TNBC) accounts for 10%-20% of breast cancers, which are characterized by the absence of estrogen receptor (ER), progesterone receptor (PR), and amplification of human epidermal growth factor receptor 2 (HER2) [2]. TNBC is well known for its rapid progressiveness, high rate of distant organ recurrence, and poor prognosis. Metastasis remains the major cause of death for patients with TNBCs. Up to date, the only direct treatment for metastatic TNBCs is chemotherapy, which has been challenged by tumor heterogeneity and drug resistance. Lack of effective targeted therapy for metastatic TNBCs impels researchers to focus on discovering potentially actionable targets through mutational profiling. Although next-generation sequencing (NGS) has shown valuable benefits in oncology, its use in metastatic TNBC demands attentions. On one hand, in view of cellular heterogeneity, the genomic profiles of tissue biopsies might not be representative for lethal tumors. There exists trauma, pain, and other safety issues when obtaining metastatic tissues in clinical practices, since metastatic TNBCs frequently involve distant organs including the liver, lungs, bones, or brain. Recently, circulating

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PIK3CB/p110β is a selective survival factor for glioblastoma

Abstract: PIK3CB/p110β is a biomarker for GBM recurrence and selectively important for GBM cell survival.

Cited by 45 publications

References 22 publications

Synergistic growth inhibition mediated by dual PI3K/mTOR pathway targeting and genetic or direct pharmacological AKT inhibition in human glioblastoma models

Synergistic growth inhibition mediated by dual PI3K/mTOR pathway targeting and genetic or direct pharmacological AKT inhibition in human glioblastoma models

Casein Kinase 1 Epsilon Regulates Glioblastoma Cell Survival

Mutational characteristics determined using circulating tumor DNA analysis in triple‐negative breast cancer patients with distant metastasis

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