ArticleProceedings of the National Academy of Sciences of the United States of America2019
Oncogenic mutations at the EGFR ectodomain structurally converge to remove a steric hindrance on a kinase-coupled cryptic epitope.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
37 citing papers in PubMed, 57 citations in OpenAlex.
- Depatuxizumab mafodotin in EGFR-amplified newly diagnosed glioblastoma: A phase III randomized clinical trial.Neuro-oncology · 2023Trial
- Integrative structural and dynamics studies of epidermal growth factor receptor (EGFR).Experimental & molecular medicine · 2026Review
- ErbB family receptor dimerization dynamics and dysregulation via long-term single-molecule imaging.Cell · 2026Article
- Efficient sampling of large-scale transition pathways and intermediate conformations in sub-mesoscopic protein complexes.Nature communications · 2026Article
- Leveraging conformational ensembles in allosteric drug discovery.Trends in pharmacological sciences · 2026Review
- The development of CAR T cells for patients with CNS malignancies.Nature reviews. Clinical oncology · 2026Review
- Glioblastoma resistance to EGFR antibody-drug conjugate is driven by transcriptional reprogramming and TEK-induced EGFR suppression.Journal of translational medicine · 2025Article
- Accurate identification and mechanistic evaluation of pathogenic missense variants withProceedings of the National Academy of Sciences of the United States of America · 2025Article
- Design of immunogens to present a tumor-specific cryptic epitope.Scientific reports · 2025Article
- Structural insights into the role and targeting of EGFRvIII.Structure (London, England : 1993) · 2024Article
- Epidermal Growth Factor Receptor Inhibitors in Glioblastoma: Current Status and Future Possibilities.International journal of molecular sciences · 2024Review
- Unraveling the Drivers of Tumorigenesis in the Context of Evolution: Theoretical Models and Bioinformatics Tools.Journal of molecular evolution · 2023Review
- An Overview of EGFR Mechanisms and Their Implications in Targeted Therapies for Glioblastoma.International journal of molecular sciences · 2023Review
- Clinical Trials in the Brain Tumour Population: Challenges and Strategies for the Future.Current oncology reports · 2023Review
- Confinement of unliganded EGFR by tetraspanin nanodomains gates EGFR ligand binding and signaling.Nature communications · 2023Article
- EGFR, the Lazarus target for precision oncology in glioblastoma.Neuro-oncology · 2022Review
- Targeting protein conformations with small molecules to control protein complexes.Trends in biochemical sciences · 2022Review
- Locally secreted BiTEs complement CAR T cells by enhancing killing of antigen heterogeneous solid tumors.Molecular therapy : the journal of the American Society of Gene Therapy · 2022Article
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Authors and funding
14 authors at 6 institutions in 6 countries.
Funding
Abstract
Epidermal growth factor receptor (EGFR) signaling is initiated by a large ligand-favored conformational change of the extracellular domain (ECD) from a closed, self-inhibited tethered monomer, to an open untethered state, which exposes a loop required for strong dimerization and activation. In glioblastomas (GBMs), structurally heterogeneous missense and deletion mutations concentrate at the ECD for unclear reasons. We explore the conformational impact of GBM missense mutations, combining elastic network models (ENMs) with multiple molecular dynamics (MD) trajectories. Our simulations reveal that the main missense class, located at the I-II interface away from the self-inhibitory tether, can unexpectedly favor spontaneous untethering to a compact intermediate state, here validated by small-angle X-ray scattering (SAXS). Significantly, such intermediate is characterized by the rotation of a large ECD fragment (N-TR1), deleted in the most common GBM mutation, EGFRvIII, and that makes accessible a cryptic epitope characteristic of cancer cells. This observation suggested potential structural equivalence of missense and deletion ECD changes in GBMs. Corroborating this hypothesis, our FACS, in vitro, and in vivo data demonstrate that entirely different ECD variants all converge to remove N-TR1 steric hindrance from the 806-epitope, which we show is allosterically coupled to an intermediate kinase and hallmarks increased oncogenicity. Finally, the detected extraintracellular coupling allows for synergistic cotargeting of the intermediate with mAb806 and inhibitors, which is proved herein.
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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.