ArticleCancer biology & therapy2009
Pro-survival AKT and ERK signaling from EGFR and mutant EGFRvIII enhances DNA double-strand break repair in human glioma cells.
Article in Cancer biology & therapy, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 104 papers.
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Who cites it
104 citing papers in PubMed, 198 citations in OpenAlex.
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- Prodigiosin in glioblastoma: mechanistic pharmacology and rationale for its development as a radiosensitiser.Frontiers in pharmacology · 2026Review
- Irradiation‑induced cellular senescence is linked to pro‑survival signaling and checkpoint regulation in a 2D and 3D model for head and neck cancer.Oncology reports · 2025Article
- Tousled-like kinase loss confers PARP inhibitor resistance in BRCA1-mutated cancers by impeding non-homologous end joining repair.Molecular medicine (Cambridge, Mass.) · 2025Article
- ATM Kinase Small Molecule Inhibitors Prevent Radiation-Induced Apoptosis of Mouse Neurons In Vivo.Kinases and phosphatases · 2024Article
- Dual p38MAPK and MEK inhibition disrupts adaptive chemoresistance in mesenchymal glioblastoma to temozolomide.Neuro-oncology · 2024Article
- PTEN-mediated dephosphorylation of 53BP1 confers cellular resistance to DNA damage in cancer cells.Molecular oncology · 2024Article
- Role of Mitogen-Activated Protein (MAP) Kinase Pathways in Metabolic Diseases.Genome integrity · 2024Review
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- PRMT5 inhibition drives therapeutic vulnerability to combination treatment with BCL-2 inhibition in mantle cell lymphoma.Blood advances · 2023Article
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- Molecular Pathways Implicated in Radioresistance of Glioblastoma Multiforme: What Is the Role of Extracellular Vesicles?International journal of molecular sciences · 2023Review
- Silibinin Radiosensitizes EGF Receptor-knockdown Prostate Cancer Cells by Attenuating DNA Repair Pathways.Journal of cancer prevention · 2022Article
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- RNF216 Alleviates Radiation-Induced Apoptosis and DNA Damage Through Regulating Ubiquitination-Mediated Degradation of p53 in Glioblastoma.Molecular neurobiology · 2022Article
- Cell Signaling Pathways That Promote Radioresistance of Cancer Cells.Diagnostics (Basel, Switzerland) · 2022Review
- Biological implications and clinical potential of invasion and migration related miRNAs in glioma.Frontiers in integrative neuroscience · 2022Review
- Chloroquine combined with concurrent radiotherapy and temozolomide for newly diagnosed glioblastoma: a phase IB trial.Autophagy · 2021Article
44 more citing papers are in PubMed but not listed here.
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Authors and funding
6 authors at 2 institutions in 2 countries.
Funding
Abstract
The epidermal growth factor receptor (EGFR) is frequently dysregulated in malignant glioma that leads to increased resistance to cancer therapy. Upregulation of wild type or expression of mutant EGFR is associated with tumor radioresistance and poor clinical outcome. EGFR variant III (EGFRvIII) is the most common EGFR mutation in malignant glioma. Radioresistance is thought to be, at least in part, the result of a strong cytoprotective response fueled by signaling via AKT and ERK that is heightened by radiation in the clinical dose range. Several groups including ours have shown that this response may modulate DNA repair. Herein, we show that expression of EGFRvIII promoted gamma-H2AX foci resolution, a surrogate for double-strand break (DSB) repair, and thus enhanced DNA repair. Conversely, small molecule inhibitors targeting EGFR, MEK, and the expression of dominant-negative EGFR (EGFR-CD533) significantly reduced the resolution of gamma-H2AX foci. When homologous recombination repair (HRR) and non-homologous end joining (NHEJ) were specifically examined, we found that EGFRvIII stimulated and CD533 compromised HRR and NHEJ, respectively. Furthermore, NHEJ was blocked by inhibitors of AKT and ERK signaling pathways. Moreover, expression of EGFRvIII and CD533 increased and reduced, respectively, the formation of phospho-DNA-PKcs and -ATM repair foci, and RAD51 foci and expression levels, indicating that DSB repair is regulated at multiple levels. Altogether, signaling from EGFR and EGFRvIII promotes both HRR and NHEJ that is likely a contributing factor towards the radioresistance of malignant gliomas.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.