ArticleProceedings of the National Academy of Sciences of the United States of America2018
Altered conformational landscape and dimerization dependency underpins the activation of EGFR by
Article in Proceedings of the National Academy of Sciences of the United States of America, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers, 1 of them a synthesis that pooled it.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
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.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
38 citing papers in PubMed, 1 synthesis or guideline pooled it, 66 citations in OpenAlex.
- Therapeutic exploration of uncommon EGFR exon 20 insertion mutations in advanced non-small cell lung cancer: breaking through brambles and thorns.Journal of cancer research and clinical oncology · 2022Pooled it
- Poziotinib for EGFR exon 20-insertion NSCLC: Clinical efficacy of the phase 2 ZENITH trial and differential impact of EGFR exon 20 insertion location on sensitivity.Nature communications · 2025Trial
- Targeting receptor tyrosine kinases: from molecular mechanisms to clinical therapeutics.Signal transduction and targeted therapy · 2026Review
- Allosteric binding cooperativity in kinases signaling, signalopathies, and drug development.Current opinion in structural biology · 2025Review
- STX-721, a Covalent EGFR/HER2 Exon 20 Inhibitor, Utilizes Exon 20-Mutant Dynamic Protein States and Achieves Unique Mutant Selectivity Across Human Cancer Models.Clinical cancer research : an official journal of the American Association for Cancer Research · 2025Article
- Prolonged survival in EGFR exon 20 insertion mutant lung adenocarcinoma: case report of sequential osimertinib and furmonertinib with research trend analysis.Frontiers in medicine · 2025Article
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- Survivin Mediates Mitotic Onset in HeLa Cells Through Activation of the Cdk1-Cdc25B Axis.Research square · 2024Article
- Approximating Projections of Conformational Boltzmann Distributions with AlphaFold2 Predictions: Opportunities and Limitations.Journal of chemical theory and computation · 2024Article
- Protein Kinase Structure and Dynamics: Role of the αC-β4 Loop.bioRxiv : the preprint server for biology · 2023Article
- Acquired Secondary HER2 Mutations Enhance HER2/MAPK Signaling and Promote Resistance to HER2 Kinase Inhibition in Breast Cancer.Cancer research · 2023Article
- Approximating conformational Boltzmann distributions with AlphaFold2 predictions.bioRxiv : the preprint server for biology · 2023Article
- Human Papillomavirus Infection andJournal of personalized medicine · 2023Article
- Structure-Guided Strategies of Targeted Therapies for Patients withBiomolecules · 2023Review
- Saturation mutagenesis of a predicted ancestral Syk-family kinase.Protein science : a publication of the Protein Society · 2022Article
- Allele-specific activation, enzyme kinetics, and inhibitor sensitivities of EGFR exon 19 deletion mutations in lung cancer.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Recognition of BRAF by CDC37 and Re-Evaluation of the Activation Mechanism for the Class 2 BRAF-L597R Mutant.Biomolecules · 2022Article
- EGFR exon 20 insertion mutations in advanced non-small-cell lung cancer: current status and perspectives.Biomarker research · 2022Review
- Article
Corrections and comments
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
Mutational activation of epidermal growth factor receptor (EGFR) in human cancers involves both point mutations and complex mutations (insertions and deletions). In particular, short in-frame insertion mutations within a conserved αC-β4 loop in the EGFR kinase domain are frequently observed in tumor samples and patients harboring these mutations are insensitive to first-generation EGFR inhibitors. Despite the prevalence and clinical relevance of insertion mutations, the mechanisms by which these mutations regulate EGFR activity and contribute to drug sensitivity are poorly understood. Using cell-based mutation screening, we find that the precise location, length, and sequence of the inserted segment are critical for ligand-independent EGFR activation and downstream signaling. We identify three insertion mutations (N771_P772insN, D770_N771insG, and D770>GY) that activate EGFR in a unique way by relying more on the "acceptor" interface for kinase activation. Our drug inhibition studies indicate that these activating insertion mutations respond more favorably to osimertinib, a recently Food and Drug Administration-approved EGFR inhibitor for T790M-positive patients with lung cancer. Molecular dynamics simulations and umbrella sampling of WT and mutant EGFR suggest a model in which activating insertion mutations increase catalytic activity by relieving key autoinhibitory interactions associated with αC-helix movement and by lowering the transition free energy ([Formula: see text]) between active and inactive states. Our studies also identify a transition state sampled by activating insertion mutations that can be exploited in the design of mutant-selective EGFR inhibitors.
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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.