NVP-BEZ235 or JAKi Treatment leads to decreased survival of examined GBM and BBC cells

Vazquez, Neftali; Lopez, Alma; Cuello, Victoria; Persans, Michael W.; Schuenzel, Erin; Innis-Whitehouse, Wendy; Keniry, Megan

doi:10.1016/j.ctarc.2021.100340

Cited by 2 publications

(3 citation statements)

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“…RNA sequencing was performed from U87MG cells treated for four days with 50 nM NVP-BEZ235 (dual PI3K-mTOR pathway inhibitor) or vehicle control with three biological replicates of each condition. This drug dose was employed in our previous studies (and others) and is not a complete inhibition of PI3K-mTOR in U87MG cells [ 31 , 33 ]. The four-day timepoint allowed us to obtain high-quality RNA for sequencing.…”

Section: Resultsmentioning

confidence: 99%

“…For example, Heinzen et al found that NVP-BEZ235 reduced growth and glucose consumption in GBM cell lines [ 32 ]. We previously investigated NVP-BEZ235 in the context of basal breast cancer and GBM and found that 50 nM NVP-BEZ235 enabled stem gene expression such as OCT4 in these settings but was also associated with decreased cell growth and apoptosis induction [ 17 , 33 ]. To better understand the molecular underpinnings for these phenotypes, we performed RNA-seq analysis with U87MG cells treated with NVP-BEZ235.…”

Section: Introductionmentioning

confidence: 99%

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PI3K Pathway Inhibition with NVP-BEZ235 Hinders Glycolytic Metabolism in Glioblastoma Multiforme Cells

Udawant

Litif

Lopez

et al. 2021

Cells

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Glioblastoma (GBM) is the most lethal primary brain cancer that lacks effective molecular targeted therapies. The PI3K/AKT/mTOR pathway is activated in 90% of all Glioblastoma multiforme (GBM) tumors. To gain insight into the impact of the PI3K pathway on GBM metabolism, we treated U87MG GBM cells with NVP-BEZ235 (PI3K and mTOR a dual inhibitor) and identified differentially expressed genes with RNA-seq analysis. RNA-seq identified 7803 differentially regulated genes in response to NVP-BEZ235. Gene Set Enrichment Analysis (GSEA) identified two glycolysis-related gene sets that were significantly enriched (p < 0.05) in control samples compared to NVP-BEZ235-treated samples. We validated the inhibition of glycolytic genes by NVP-BEZ235 and examined the impact of the FOXO1 inhibitor (AS1842856) on these genes in a set of GBM cell lines. FOXO1 inhibition alone was associated with reduced LDHA expression, but not ENO1 or PKM2. Bioinformatics analyses revealed that PI3K-impacted glycolytic genes were over-expressed and co-expressed in GBM clinical samples. The elevated expression of PI3K-impacted glycolytic genes was associated with poor prognosis in GBM based on Kaplan–Meier survival analyses. Our results suggest novel insights into hallmark metabolic reprogramming associated with the PI3K-mTOR dual inhibition.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

PI3K Pathway Inhibition with NVP-BEZ235 Hinders Glycolytic Metabolism in Glioblastoma Multiforme Cells

Udawant

Litif

Lopez

et al. 2021

Cells

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“…Mild results were obtained by Giorgi et al (2018), and when OS cells were treated with a similar inhibitor range, U2-OS and MG63 presented no significant differences in apoptosis induction, although the drug was efficacious with either doxorubicin or vincristine [ 774 , 775 , 776 ]. In RB, GBM, and MB, decreased viability and proliferation in a dose-dependent pattern was observed in most cell lines [ 777 , 778 , 779 , 780 ]. When tested in vivo, dactolisib could reduce tumor volume, vascularity and metastasis and improve animal survival, especially when combined with other drugs, such as topotecan, carboplatin, vincristine or the SMO inhibitor LDE225 [ 773 , 781 , 782 , 783 ].…”

Section: Kinases As Druggable Targets—evidence and Limitationsmentioning

confidence: 99%

Drugging Hijacked Kinase Pathways in Pediatric Oncology: Opportunities and Current Scenario

et al. 2023

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Childhood cancer is considered rare, corresponding to ~3% of all malignant neoplasms in the human population. The World Health Organization (WHO) reports a universal occurrence of more than 15 cases per 100,000 inhabitants around the globe, and despite improvements in diagnosis, treatment and supportive care, one child dies of cancer every 3 min. Consequently, more efficient, selective and affordable therapeutics are still needed in order to improve outcomes and avoid long-term sequelae. Alterations in kinases’ functionality is a trademark of cancer and the concept of exploiting them as drug targets has burgeoned in academia and in the pharmaceutical industry of the 21st century. Consequently, an increasing plethora of inhibitors has emerged. In the present study, the expression patterns of a selected group of kinases (including tyrosine receptors, members of the PI3K/AKT/mTOR and MAPK pathways, coordinators of cell cycle progression, and chromosome segregation) and their correlation with clinical outcomes in pediatric solid tumors were accessed through the R2: Genomics Analysis and Visualization Platform and by a thorough search of published literature. To further illustrate the importance of kinase dysregulation in the pathophysiology of pediatric cancer, we analyzed the vulnerability of different cancer cell lines against their inhibition through the Cancer Dependency Map portal, and performed a search for kinase-targeted compounds with approval and clinical applicability through the CanSAR knowledgebase. Finally, we provide a detailed literature review of a considerable set of small molecules that mitigate kinase activity under experimental testing and clinical trials for the treatment of pediatric tumors, while discuss critical challenges that must be overcome before translation into clinical options, including the absence of compounds designed specifically for childhood tumors which often show differential mutational burdens, intrinsic and acquired resistance, lack of selectivity and adverse effects on a growing organism.

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NVP-BEZ235 or JAKi Treatment leads to decreased survival of examined GBM and BBC cells

Cited by 2 publications

References 102 publications

PI3K Pathway Inhibition with NVP-BEZ235 Hinders Glycolytic Metabolism in Glioblastoma Multiforme Cells

PI3K Pathway Inhibition with NVP-BEZ235 Hinders Glycolytic Metabolism in Glioblastoma Multiforme Cells

Drugging Hijacked Kinase Pathways in Pediatric Oncology: Opportunities and Current Scenario

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