Therapeutic Inhibition of the Epidermal Growth Factor Receptor in High-Grade Gliomas: Where Do We Stand?

Karpel‐Massler, Georg; Schmidt, U; Unterberg, Andreas; Halatsch, Marc‐Eric

doi:10.1158/1541-7786.mcr-08-0479

Cited by 113 publications

(99 citation statements)

References 122 publications

(123 reference statements)

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“…9,10 TKIs, e.g., erlotinib, gefitinib, PKI166, lapatanib, pelitinib and canertinib, are small molecules that mechanistically compete for the ATP-binding site in the TK domain of EGFR, thereby resulting in the ablation of both phosphorylation of the receptor and downstream signaling. 3,11 The combination of these targeted agents with chemotherapy and/or radiotherapy may represent an attractive solution against GBMs and are currently evaluated in clinical trials for their efficacy for newly diagnosed and recurrent GBM. 12 Erlotinib is orally active and represents the best explored TK inhibitors in the clinic for the treatment of GBM.…”

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confidence: 99%

“…12 Erlotinib is orally active and represents the best explored TK inhibitors in the clinic for the treatment of GBM. 11 A recent study reported that a subset of GBM patients with MGMT promoter methylation and PTEN positivity showed significantly longer survival with the treatment of erlotinib in combination with radiotherapy and temozolomide. 13 However, most studies have shown very modest or no significant survival benefit from TKIs due to the recurrent problem of resistance caused by mutations in EGFR or tumor heterogeneity.…”

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confidence: 99%

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Shikonin and its derivatives inhibit the epidermal growth factor receptor signaling and synergistically kill glioblastoma cells in combination with erlotinib

et al. 2015

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Overexpression and mutation of the epidermal growth factor receptor (EGFR) gene play a causal role in tumorigenesis and resistance to treatment of glioblastoma (GBM). EGFR inhibitors such as erlotinib are currently used for the treatment of GBM; however, their efficacy has been limited due to drug resistance. New treatment strategies are therefore urgently needed. Shikonin, a natural naphthoquinone, induces both apoptosis and necroptosis in human glioma cells, but the effectiveness of erlotinib-shikonin combination treatment as well as the underlying molecular mechanisms is unknown yet. In this study, we investigated erlotinib in combination with shikonin and 14 shikonin derivatives in parental U87MG and transfected U87MG.DEGFR GBM cells. Most of the shikonin derivatives revealed strong cytotoxicity. Shikonin together with five other derivatives, namely deoxyshikonin, isobutyrylshikonin, acetylshikonin, b,b-dimethylacrylshikonin and acetylalkannin showed synergistic cytotoxicity toward U87MG.DEGFR in combination with erlotinib. Moreover, the combined cytotoxic effect of shikonin and erlotinib was further confirmed with another three EGFR-expressing cell lines, BS153, A431 and DK-MG. Shikonin not only dose-dependently inhibited EGFR phosphorylation and decreased phosphorylation of EGFR downstream molecules, including AKT, P44/42MAPK and PLCc1, but also together with erlotinib synergistically inhibited DEGFR phosphorylation in U87MG.DEGFR cells as determined by Loewe additivity and Bliss independence drug interaction models. These results suggest that the combination of erlotinib with shikonin or its derivatives might be a potential strategy to overcome drug resistance to erlotinib.Glioblastoma (GBM) is the most common primary brain tumor in adults and one of the deadliest human cancers with a median survival rate of 12 months despite aggressive therapies (i.e., urgical resection, radiotherapy and chemotherapy) due to their highly invasive and neurologically destructive nature.

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Shikonin and its derivatives inhibit the epidermal growth factor receptor signaling and synergistically kill glioblastoma cells in combination with erlotinib

et al. 2015

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“…The HER1/EGFR is overexpressed in more than 50% of glioblastoma, which was shown to be associated with enhanced tumorigenicity and tumor growth in preclinical models of this disease (4)(5)(6)(7). For that reason, HER1/EGFR was considered a promising molecular target for glioblastoma therapy, and a variety of HER1/EGFR-targeted agents were developed, including small-molecule tyrosine kinase inhibitors such as erlotinib (Tarceva; Genentech Inc.; reviewed in ref.…”

Section: Introductionmentioning

confidence: 99%

“…For that reason, HER1/EGFR was considered a promising molecular target for glioblastoma therapy, and a variety of HER1/EGFR-targeted agents were developed, including small-molecule tyrosine kinase inhibitors such as erlotinib (Tarceva; Genentech Inc.; reviewed in ref. 4). Erlotinib competitively inhibits the binding of ATP to the intracellular catalytic tyrosine kinase domain of the receptor and suppresses subsequent autophosphorylation and downward signaling via phosphoinositide 3-kinase/murine thymoma viral oncogene homolog (PI3K/AKT) and mitogen-activated protein kinase (MAPK) pathways (8,9).…”

Section: Introductionmentioning

confidence: 99%

Combined Inhibition of HER1/EGFR and RAC1 Results in a Synergistic Antiproliferative Effect on Established and Primary Cultured Human Glioblastoma Cells

Karpel‐Massler

Westhoff

Zhou

et al. 2013

Molecular Cancer Therapeutics

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Glioblastoma is the most frequent brain tumor of glial origin in adults. With the best available standard-ofcare, patients with this disease have a life expectancy of only approximately 15 months after diagnosis. Because the EGF receptor (HER1/EGFR) is one of the most commonly dysregulated oncogenes in glioblastoma, HER1/ EGFR-targeted agents, such as erlotinib, were expected to provide a therapeutic benefit. However, their application in the clinical setting failed. Seeking an explanation for this finding, we previously identified several candidate genes for resistance of human glioblastoma cell lines toward erlotinib. On the basis of this panel of genes, we aimed at identifying drugs that synergistically enhance the antiproliferative effect of erlotinib on established and primary glioblastoma cell lines. We found that NSC23766, an inhibitor of RAC1, enhanced the antineoplastic effects of erlotinib in U87MG, T98MG, and A172MG glioblastoma cell lines for the most part in a synergistic or at least in an additive manner. In addition, the synergistic antiproliferative effect of erlotinib and NSC23766 was confirmed in primary cultured cells, indicating a common underlying cellular and molecular mechanism in glioblastoma. Therefore, agents that suppress RAC1 activation may be useful therapeutic partners for erlotinib in a combined targeted treatment of glioblastoma.

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“…EGFR has received much attention as a potential target for GBM treatment because of its high frequency of mutation, genomic and expression alterations causing increased protein expression and activated signaling [203,204]. Almost 40% of GBMs have overactivated EGFR [18].…”

Section: Introductionmentioning

confidence: 99%

Identification and Characterization of miR-148a as a New Oncogenic and Prognostic microRNA in Glioblastoma

Kim

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Great interest persists in useful prognostic and therapeutic targets in glioblastoma (GBM), the most common and most deadly human brain tumor. In this study, we report the identification and characterization of microRNA-148a (miR-148a) as a novel prognostic oncomiR in GBM. We show that miR-148a expression is elevated in human GBM specimens, cell lines, and stem cells (GSC) compared with normal human brain and astrocytes. High levels of miR-148a were a risk indicator for GBM patient survival. Functionally, miR-148a expression increased cell growth, survival, migration, and invasion in glioblastoma cells and GSCs and promoted GSC neurosphere formation. We identified two direct targets of miR-148a, the EGF receptor (EGFR) regulator MIG6 and the apoptosis regulator BIM. Rescue experiments showed that MIG6 and BIM were essential to mediate the oncogenic activity of miR-148a. By inhibiting MIG6 expression, miR148a reduced EGFR trafficking to Rab7-expressing compartments, which includes late endosomes and lysosomes. This process coincided with reduced degradation and elevated expression and activation of EGFR. Finally, inhibition of miR-148a strongly suppressed GSC and glioblastoma xenograft growth in vivo. Taken together, our findings provide a comprehensive analysis of the prognostic value and oncogenic function of miR-148a in glioblastoma, further defining it as a potential target for glioblastoma therapy.

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Therapeutic Inhibition of the Epidermal Growth Factor Receptor in High-Grade Gliomas: Where Do We Stand?

Abstract: High-grade gliomas account for the majority of intra-axial brain tumors. Despite abundant therapeutic efforts, clinical outcome is still poor. Thus, new therapeutic approaches are intensely being investigated.

Cited by 113 publications

References 122 publications

Shikonin and its derivatives inhibit the epidermal growth factor receptor signaling and synergistically kill glioblastoma cells in combination with erlotinib

Shikonin and its derivatives inhibit the epidermal growth factor receptor signaling and synergistically kill glioblastoma cells in combination with erlotinib

Combined Inhibition of HER1/EGFR and RAC1 Results in a Synergistic Antiproliferative Effect on Established and Primary Cultured Human Glioblastoma Cells

Identification and Characterization of miR-148a as a New Oncogenic and Prognostic microRNA in Glioblastoma

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