AKT Pathway Genes Define 5 Prognostic Subgroups in Glioblastoma

Joy, Anna; Ramesh, Archana; Смирнов, Иван; Reiser, Mark; Misra, Ankita; Shapiro, William R.; Mills, Gordon B.; S, Kim; Feuerstein, Burt G.

doi:10.1371/journal.pone.0100827

Cited by 12 publications

(5 citation statements)

References 51 publications

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“…PIK3CB is a catalytic subunit of PI3K complex [ 36 ]. The PI3K/AKT pathway has been implicated in GBM recurrence and its inhibitors have been used to treat recurrent tumors [ 37 , 38 ]. We then analyzed multiple kinases in or downstream of this pathway.…”

Section: Resultsmentioning

confidence: 99%

Survival kinase genes present prognostic significance in glioblastoma

et al. 2016

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Cancer biomarkers with a strong predictive power for diagnosis/prognosis and a potential to be therapeutic targets have not yet been fully established. Here we employed a loss-of-function screen in glioblastoma (GBM), an infiltrative brain tumor with a dismal prognosis, and identified 20 survival kinase genes (SKGs). Survival analyses using The Cancer Genome Atlas (TCGA) datasets revealed that the expression of CDCP1, CDKL5, CSNK1E, IRAK3, LATS2, PRKAA1, STK3, TBRG4, and ULK4 stratified GBM prognosis with or without temozolomide (TMZ) treatment as a covariate. For the first time, we found that GBM patients with a high level of NEK9 and PIK3CB had a greater chance of having recurrent tumors. The expression of CDCP1, IGF2R, IRAK3, LATS2, PIK3CB, ULK4, or VRK1 in primary GBM tumors was associated with recurrence-related prognosis. Notably, the level of PIK3CB in recurrent tumors was much higher than that in newly diagnosed ones. Congruent with these results, genes in the PI3K/AKT pathway showed a significantly strong correlation with recurrence rate, further highlighting the pivotal role of PIK3CB in the disease progression. Importantly, 17 SKGs together presented a novel GBM prognostic signature. SKGs identified herein are associated with recurrence rate and present prognostic significance in GBM, thereby becoming attractive therapeutic targets.

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Section: Resultsmentioning

confidence: 99%

Survival kinase genes present prognostic significance in glioblastoma

et al. 2016

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“…An AKT pathway based classification suggested 5 AKT GBM subtypes [27]. Patients in one of the AKT-based subtypes, the SL subtype, were younger and lived approximately 3 years longer than patients in other subtypes [27]. This subtype also included tumors with the good prognostic factor, mutant IDH1.…”

Section: Resultsmentioning

confidence: 99%

The role of AKT isoforms in glioblastoma: AKT3 delays tumor progression

et al. 2016

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The growth factor receptor/PI3K/AKT pathway is an important drug target in many cancers including Glioblastoma. AKT, a key node in the pathway, has 3 isoforms, AKT1, AKT2 and AKT3. Here we investigate their role in GBM. We find each activated, ser473 phosphorylated isoform is present in some GBMs but expression patterns vary. There is a direct relationship between human GBM patient outcome and both AKT1 and AKT2 mRNA levels, but an inverse relationship with AKT3 mRNA. Furthermore, AKT3 mRNA levels were high in a less aggressive GBM subtype. Overexpressing AKT3 improves survival in a rodent model of GBM and decreases colony forming efficiency, but not growth rate, in glioma cells. Silencing AKT3 slows cell cycle progression in one cell line and increases apoptosis in another. Our studies of AKT3 substrates indicate (1) silencing both AKT2 and AKT3 reduces GSK3 phosphorylation (2) only AKT2 silencing reduces S6 phosphorylation. Since S6 phosphorylation is a marker of mTORC1 activity this indicates that AKT2 activates mTORC1, but AKT3 does not. Our results indicate AKT isoforms have different roles and downstream substrates in GBM. Unexpectedly, they indicate AKT3 delays tumor progression. Therefore strategies that inhibit AKT3 may be unhelpful in some GBM patients.

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“…The TCGA study found that almost 10% of the GBMs had mutations in the PIK3R1, which has not been found to be frequently expressed in any other cancer [ 53 ]. Furthermore, it has been reported that AKT classification can be a predictive marker that identifies a subset of GBM patients responding to carmustine (BCNU)/CCNU and PI3K/AKT/mTOR pathway inhibitors [ 54 ]. More recent studies have revealed that the tumor suppressor gene NF1, that encodes neurofibromin (RAS negative regulator), is mutated/deleted in 15% to 18% of primary GBMs (mesenchymal subclass) [ 53 , 55 ].…”

Section: Rtk Signaling In Gbmmentioning

confidence: 99%

Diagnostic and Therapeutic Biomarkers in Glioblastoma: Current Status and Future Perspectives

Szopa

Burley

Kramer‐Marek

et al. 2017

BioMed Research International

253

220

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Glioblastoma (GBM) is a primary neuroepithelial tumor of the central nervous system, characterized by an extremely aggressive clinical phenotype. Patients with GBM have a poor prognosis and only 3–5% of them survive for more than 5 years. The current GBM treatment standards include maximal resection followed by radiotherapy with concomitant and adjuvant therapies. Despite these aggressive therapeutic regimens, the majority of patients suffer recurrence due to molecular heterogeneity of GBM. Consequently, a number of potential diagnostic, prognostic, and predictive biomarkers have been investigated. Some of them, such as IDH mutations, 1p19q deletion, MGMT promoter methylation, and EGFRvIII amplification are frequently tested in routine clinical practice. With the development of sequencing technology, detailed characterization of GBM molecular signatures has facilitated a more personalized therapeutic approach and contributed to the development of a new generation of anti-GBM therapies such as molecular inhibitors targeting growth factor receptors, vaccines, antibody-based drug conjugates, and more recently inhibitors blocking the immune checkpoints. In this article, we review the exciting progress towards elucidating the potential of current and novel GBM biomarkers and discuss their implications for clinical practice.

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AKT Pathway Genes Define 5 Prognostic Subgroups in Glioblastoma

Cited by 12 publications

References 51 publications

Survival kinase genes present prognostic significance in glioblastoma

Survival kinase genes present prognostic significance in glioblastoma

The role of AKT isoforms in glioblastoma: AKT3 delays tumor progression

Diagnostic and Therapeutic Biomarkers in Glioblastoma: Current Status and Future Perspectives

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