PIK3CA missense mutations promote glioblastoma pathogenesis, but do not enhance targeted PI3K inhibition

McNeill, Robert S.; Stroobant, Emily E.; Smithberger, Erin; Canoutas, Demitra A.; Butler, Madison; Shelton, Abigail; Patel, Shrey; Limas, Juanita C.; Skinner, Kasey R; Bash, Ryan; Schmid, Ralf S.; Miller, C. Ryan

doi:10.1371/journal.pone.0200014

Cited by 20 publications

(18 citation statements)

References 54 publications

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“…It has been suggested that glioblastoma cell lines with helical domain mutations are still sensitive to dual PI3Ki/MEKi treatment [9], which is consistent with our observation that the EGFR-signaling pathway is adjustable in cell line SF767. Also, it has been found that Gefitinib inhibited EGFR phosphorylation in U251MG and SF767 cells, whereas Gefitinib inhibited AKT phosphorylation only in SF767 cells but not in U251MG cells [18], consistent to Fig.…”

Section: Discussionsupporting

confidence: 92%

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Prediction of regulatory targets of alternative isoforms of the epidermal growth factor receptor in a glioblastoma cell line

et al. 2019

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Background The epidermal growth factor receptor (EGFR) is a major regulator of proliferation in tumor cells. Elevated expression levels of EGFR are associated with prognosis and clinical outcomes of patients in a variety of tumor types. There are at least four splice variants of the mRNA encoding four protein isoforms of EGFR in humans, named I through IV. EGFR isoform I is the full-length protein, whereas isoforms II-IV are shorter protein isoforms. Nevertheless, all EGFR isoforms bind the epidermal growth factor (EGF). Although EGFR is an essential target of long-established and successful tumor therapeutics, the exact function and biomarker potential of alternative EGFR isoforms II-IV are unclear, motivating more in-depth analyses. Hence, we analyzed transcriptome data from glioblastoma cell line SF767 to predict target genes regulated by EGFR isoforms II-IV, but not by EGFR isoform I nor other receptors such as HER2, HER3, or HER4. Results We analyzed the differential expression of potential target genes in a glioblastoma cell line in two nested RNAi experimental conditions and one negative control, contrasting expression with EGF stimulation against expression without EGF stimulation. In one RNAi experiment, we selectively knocked down EGFR splice variant I, while in the other we knocked down all four EGFR splice variants, so the associated effects of EGFR II-IV knock-down can only be inferred indirectly. For this type of nested experimental design, we developed a two-step bioinformatics approach based on the Bayesian Information Criterion for predicting putative target genes of EGFR isoforms II-IV. Finally, we experimentally validated a set of six putative target genes, and we found that qPCR validations confirmed the predictions in all cases. Conclusions By performing RNAi experiments for three poorly investigated EGFR isoforms, we were able to successfully predict 1140 putative target genes specifically regulated by EGFR isoforms II-IV using the developed Bayesian Gene Selection Criterion (BGSC) approach. This approach is easily utilizable for the analysis of data of other nested experimental designs, and we provide an implementation in R that is easily adaptable to similar data or experimental designs together with all raw datasets used in this study in the BGSC repository, https://github.com/GrosseLab/BGSC . Electronic supplementary material The online version of this article (10.1186/s12859-019-2944-9) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 92%

“…A meaningful analysis of the EGFR-signaling pathway is possible only in a cell line with an adjustable pathway, e.g., by a response to ligand stimulation or treatment by a tyrosine kinase inhibitor (TKI) [9]. Hence, we investigated four glioblastoma cell lines in a pilot study to identify a cell line with an adjustable EGFR-signaling pathway.…”

Section: Resultsmentioning

confidence: 99%

Prediction of regulatory targets of alternative isoforms of the epidermal growth factor receptor in a glioblastoma cell line

et al. 2019

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“…Jiang et al demonstrated that PTEN mutations are associated with therapeutic resistance [31]; while Benitez et al demonstrated that PTEN regulates GBM oncogenesis [32]. Mutations in the PIK3R1gene have been shown to promote the growth and formation of gliomas [33], while PIK3CA missense mutations have been shown to promote GBM pathogenesis [34].…”

Section: Selection Of Mutated Genes For Personalisationmentioning

confidence: 99%

“…Only GBM 5 contained variants of the PIK3CA gene (Figure 2). Missense mutations in this gene have been shown to make GBMs more sensitive to treatment with a combination containing a phosphoinositide 3-kinase (P3K) inhibitor and a mitogen-activated protein kinase (MEK) inhibitor [34]. CEL has been shown to be both a P3K and MEK inhibitor [50,51], thus removing it from the combination reduced the combinations efficacy against GBM 5 ( Figure 3B).…”

Section: The Influence Of Personalisation On Cell Viabilitymentioning

confidence: 99%

The Personalisation of Glioblastoma Treatment Using Whole Exome Sequencing: A Pilot Study

Garrett

Lastakchi

McConville

2020

Genes

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The molecular heterogeneity of glioblastoma has been linked to differences in survival and treatment response, while the development of personalised treatments may be a novel way of combatting this disease. Here we show for the first time that low passage number cells derived from primary tumours are greater than an 86% match genetically to the tumour tissue. We used these cells to identify eight genes that could be used for the personalisation of glioblastoma treatment and discovered a number of personalised drug combinations that were significantly more effective at killing glioblastoma cells and reducing recurrence than the individual drugs as well as the control and non-personalised combinations. This pilot study demonstrates for the first time that whole exome sequencing has the potential be used to improve the treatment of glioblastoma patients by personalising treatment. This novel approach could potentially offer a new avenue for treatment for this terrible disease.

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“…The PI3K pathway is also activated by gain-of-function mutations in the PI3K catalytic subunit gene (PIK3CA). These mutations occur in up to 10% of GBMs and result in constitutive activation of the pathway with downstream effects similar to those promoted by EGFRvIII and PTEN mutations [81]. The key role of PI3K-Akt pathway in oncogenesis has sparked increasing interest in using small molecular inhibitors to target this pathway.…”

Section: The Molecular Hallmarks Of Invasion In Gbmmentioning

confidence: 99%

Molecular and Clinical Insights into the Invasive Capacity of Glioblastoma Cells

Velásquez

Mansouri

Mora

et al. 2019

Journal of Oncology

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The invasive capacity of GBM is one of the key tumoral features associated with treatment resistance, recurrence, and poor overall survival. The molecular machinery underlying GBM invasiveness comprises an intricate network of signaling pathways and interactions with the extracellular matrix and host cells. Among them, PI3k/Akt, Wnt, Hedgehog, and NFkB play a crucial role in the cellular processes related to invasion. A better understanding of these pathways could potentially help in developing new therapeutic approaches with better outcomes. Nevertheless, despite significant advances made over the last decade on these molecular and cellular mechanisms, they have not been translated into the clinical practice. Moreover, targeting the infiltrative tumor and its significance regarding outcome is still a major clinical challenge. For instance, the pre- and intraoperative methods used to identify the infiltrative tumor are limited when trying to accurately define the tumor boundaries and the burden of tumor cells in the infiltrated parenchyma. Besides, the impact of treating the infiltrative tumor remains unclear. Here we aim to highlight the molecular and clinical hallmarks of invasion in GBM.

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PIK3CA missense mutations promote glioblastoma pathogenesis, but do not enhance targeted PI3K inhibition

Cited by 20 publications

References 54 publications

Prediction of regulatory targets of alternative isoforms of the epidermal growth factor receptor in a glioblastoma cell line

Prediction of regulatory targets of alternative isoforms of the epidermal growth factor receptor in a glioblastoma cell line

The Personalisation of Glioblastoma Treatment Using Whole Exome Sequencing: A Pilot Study

Molecular and Clinical Insights into the Invasive Capacity of Glioblastoma Cells

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