Updated Insights on EGFR Signaling Pathways in Glioma

Opriţa, Alexandru; Baloi, Stefania-Carina; Staicu, Georgiana-Adeline; Alexandru, Oana; Tache, Daniela Elise; Dănoiu, Suzana; Micu, Elena Simona; Sevastre, Ani-Simona

doi:10.3390/ijms22020587

Cited by 78 publications

(51 citation statements)

References 145 publications

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“…In conclusion, our data strongly indicate that, in GBMs, S1P production and release by EGRF+ cells downstream of the EGFRvIII-ERK-SK1-S1P 1 pathway is involved in the pathogenic resistance to TMZ linked to EGFR overexpression and activation. All together, these results could partially explain the resistance of GBMs to treatments targeting EGFR [44]; in addition, our data further support the fundamental relevance of S1P signaling as a therapeutic target in these brain tumors. Thus, it is plausible that therapies targeting both S1P and EGFR signaling would be more effective strategies in the treatment of GBMs.…”

Section: Discussionsupporting

confidence: 77%

“…Moreover, S1P has been shown to transactivate EGF/IGF receptor signaling pathways, resulting in increased GBM cell proliferation and tumor growth [43]. In particular, EGFR, in turn, hyperactivates the phosphatidylinositol 3 kinase (PI3K)/AKT signaling pathway, which is involved in the regulation of glioma cell survival, proliferation and motility [44]. The constitutively active mutant form of EGFR, EGFRvIII, occurs frequently in GBM and confers a growth advantage to these tumors [44,45].…”

Section: Discussionmentioning

confidence: 99%

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Extracellular Sphingosine-1-Phosphate Downstream of EGFR Increases Human Glioblastoma Cell Survival

Bassi

Brambilla

Tringali

et al. 2021

IJMS

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Sphingosine-1-phosphate (S1P) is a crucial mediator involved in the progression of different cancers, including glioblastoma multiforme (GBM), the most frequent and deadly human brain tumor, characterized by extensive invasiveness and rapid cell growth. Most of GBMs overexpress the epidermal growth factor receptor (EGFR), and we investigated the possible link between S1P and EGFR signaling pathways, focusing on its role in GBM survival, using the U87MG human cell line overexpressing EGFR (EGFR+). We previously demonstrated that EGFR+ cells have higher levels of extracellular S1P and increased sphingosine kinase-1 (SK1) activity than empty vector expressing cells. Notably, we demonstrated that EGFR+ cells are resistant to temozolomide (TMZ), the standard chemotherapeutic drug in GBM treatment, and the inhibition of SK1 or S1P receptors made EGFR+ cells sensitive to TMZ; moreover, exogenous S1P reverted this effect, thus involving extracellular S1P as a survival signal in TMZ resistance in GBM cells. In addition, both PI3K/AKT and MAPK inhibitors markedly reduced cell survival, suggesting that the enhanced resistance to TMZ of EGFR+ cells is dependent on the increased S1P secretion, downstream of the EGFR-ERK-SK1-S1P pathway. Altogether, our study provides evidence of a functional link between S1P and EGFR signaling pathways enhancing the survival properties of GBM cells.

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Section: Discussionsupporting

confidence: 77%

Section: Discussionmentioning

confidence: 99%

Extracellular Sphingosine-1-Phosphate Downstream of EGFR Increases Human Glioblastoma Cell Survival

Bassi

Brambilla

Tringali

et al. 2021

IJMS

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“…EGFR can be activated by numerous ligands such as EGF, TGFα, heparin-binding EGF-like growth factor (HB-EGF), amphiregulin and epiregulin. Stimulation of the EGFR dependent signaling pathways, PI3K-AKT and mTOR, MAPK-Erk, or JAK/STAT, transduces signals into the nucleus, leading to gene expression changes that are responsible for tumor proliferation, genetic immortality, invasion, angiogenesis, and the avoidance of immune surveillance [177]. ErbB3 and ErbB4 bind neuregulins are activating signaling pathways with antiproliferative and differentiating effects.…”

Section: A Connection Between Gbm Tumorigenesis Egfr Signaling and Pkc Isozymesmentioning

confidence: 99%

Targeting Protein Kinase C in Glioblastoma Treatment

et al. 2021

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Glioblastoma (GBM) is the most frequent and aggressive primary brain tumor and is associated with a poor prognosis. Despite the use of combined treatment approaches, recurrence is almost inevitable and survival longer than 14 or 15 months after diagnosis is low. It is therefore necessary to identify new therapeutic targets to fight GBM progression and recurrence. Some publications have pointed out the role of glioma stem cells (GSCs) as the origin of GBM. These cells, with characteristics of neural stem cells (NSC) present in physiological neurogenic niches, have been proposed as being responsible for the high resistance of GBM to current treatments such as temozolomide (TMZ). The protein Kinase C (PKC) family members play an essential role in transducing signals related with cell cycle entrance, differentiation and apoptosis in NSC and participate in distinct signaling cascades that determine NSC and GSC dynamics. Thus, PKC could be a suitable druggable target to treat recurrent GBM. Clinical trials have tested the efficacy of PKCβ inhibitors, and preclinical studies have focused on other PKC isozymes. Here, we discuss the idea that other PKC isozymes may also be involved in GBM progression and that the development of a new generation of effective drugs should consider the balance between the activation of different PKC subtypes.

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“…The most frequent genetic aberration associated with malignant glioma is an amplification of the EGFR, also referred to as ERBB1 or human epidermal receptor 1 (HER1), and the expression of the EGFR variant III (EGFRvIII). Updated insights on EGFR signaling pathways in glioma have recently been reviewed [ 70 ]. Due to the important role of the EGFR pathway in glioma, the interest in therapeutically targeting EGFR increased rapidly over the past few decades.…”

Section: Receptor Tyrosine Kinase Inhibitors (Rtkis) For Gb Therapymentioning

confidence: 99%

Novel Receptor Tyrosine Kinase Pathway Inhibitors for Targeted Radionuclide Therapy of Glioblastoma

et al. 2021

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Glioblastoma (GB) remains the most fatal brain tumor characterized by a high infiltration rate and treatment resistance. Overexpression and/or mutation of receptor tyrosine kinases is common in GB, which subsequently leads to the activation of many downstream pathways that have a critical impact on tumor progression and therapy resistance. Therefore, receptor tyrosine kinase inhibitors (RTKIs) have been investigated to improve the dismal prognosis of GB in an effort to evolve into a personalized targeted therapy strategy with a better treatment outcome. Numerous RTKIs have been approved in the clinic and several radiopharmaceuticals are part of (pre)clinical trials as a non-invasive method to identify patients who could benefit from RTKI. The latter opens up the scope for theranostic applications. In this review, the present status of RTKIs for the treatment, nuclear imaging and targeted radionuclide therapy of GB is presented. The focus will be on seven tyrosine kinase receptors, based on their central role in GB: EGFR, VEGFR, MET, PDGFR, FGFR, Eph receptor and IGF1R. Finally, by way of analyzing structural and physiological characteristics of the TKIs with promising clinical trial results, four small molecule RTKIs were selected based on their potential to become new therapeutic GB radiopharmaceuticals.

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Updated Insights on EGFR Signaling Pathways in Glioma

Cited by 78 publications

References 145 publications

Extracellular Sphingosine-1-Phosphate Downstream of EGFR Increases Human Glioblastoma Cell Survival

Extracellular Sphingosine-1-Phosphate Downstream of EGFR Increases Human Glioblastoma Cell Survival

Targeting Protein Kinase C in Glioblastoma Treatment

Novel Receptor Tyrosine Kinase Pathway Inhibitors for Targeted Radionuclide Therapy of Glioblastoma

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