ArticleClinical cancer research : an official journal of the American Association for Cancer Research2019
On-target Resistance to the Mutant-Selective EGFR Inhibitor Osimertinib Can Develop in an Allele-Specific Manner Dependent on the Original EGFR-Activating Mutation.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 62 papers.
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Who cites it
62 citing papers in PubMed.
- Pilot Study of Dacomitinib for Patients With MetastaticJCO precision oncology · 2021Trial
- Saturation profiling of drug-resistant genetic variants using prime editing.Nature biotechnology · 2025Article
- Cell Death, Molecular Targeted Therapies, and Metabolic Reprogramming in EGFR-Mutant Lung Cancer.Cancers · 2025Review
- Personalized cancer treatment strategies incorporating irreversible and reversible drug resistance mechanisms.NPJ systems biology and applications · 2025Article
- SKA3 promotes lung adenocarcinoma progression via the EGFR/E2F1/SKA3/integrin β1 signaling loop.Molecular and cellular biochemistry · 2025Article
- Basal-shift transformation leads to EGFR therapy-resistance in human lung adenocarcinoma.Nature communications · 2025Article
- Responsiveness of different MET tumour alterations to type I and type II MET inhibitors.Clinical and translational medicine · 2025Article
- Strategies to Overcome Resistance to Osimertinib in EGFR-Mutated Lung Cancer.International journal of molecular sciences · 2025Review
- Optimizing Osimertinib for NSCLC: Targeting Resistance and Exploring Combination Therapeutics.Cancers · 2025Review
- Osimertinib acquired resistance among patients with EGFR-mutated NSCLC: from molecular mechanisms to clinical therapeutic strategies.Cancer drug resistance (Alhambra, Calif.) · 2025Review
- Article
- Enhancing Lung Cancer Care in Portugal: Bridging Gaps for Improved Patient Outcomes.Journal of personalized medicine · 2024Review
- Approximating Projections of Conformational Boltzmann Distributions with AlphaFold2 Predictions: Opportunities and Limitations.Journal of chemical theory and computation · 2024Article
- Characterization of Patients withOncoTargets and therapy · 2024Article
- Mechanisms of resistance to targeted therapy and immunotherapy in non-small cell lung cancer: promising strategies to overcoming challenges.Frontiers in immunology · 2024Review
- Repeat biopsy versus initial biopsy in terms of complication risk factors and clinical outcomes for patients with non-small cell lung cancer: a comparative study of 113 CT-guided needle biopsy of lung lesions.Frontiers in oncology · 2024Article
- The FLT3American journal of hematology · 2023Article
- Clinical Efficacy and Safety of First- or Second-Generation EGFR-TKIs after Osimertinib Resistance for EGFR Mutated Lung Cancer: A Prospective Exploratory Study.Targeted oncology · 2023Observational
- Approximating conformational Boltzmann distributions with AlphaFold2 predictions.bioRxiv : the preprint server for biology · 2023Article
- Efficacy of Osimertinib in Patients with Lung Cancer Positive for Uncommon EGFR Exon 19 Deletion Mutations.Clinical cancer research : an official journal of the American Association for Cancer Research · 2023Article
2 more citing papers are in PubMed but not listed here.
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Authors and funding
15 authors.
Funding
Abstract
purposeThe third-generation EGFR inhibitor, osimertinib, is the first mutant-selective inhibitor that has received regulatory approval for the treatment of patients with
resultsOur simulations suggest that the G724S mutation selectively reduces osimertinib-binding affinity in the context of Ex19Del. Consistent with our simulations, cell lines transduced with Ex19Del/G724S demonstrate resistance to osimertinib, whereas cells transduced with L858R/G724S are sensitive to osimertinib. Subsequent clinical genomic profiling data further suggest G724S occurs with Ex19Del but not L858R. Furthermore, we demonstrate that Ex19Del/G724S retains sensitivity to afatinib, but not to erlotinib, suggesting a possible therapy for patients at the time of disease relapse.
conclusionsAltogether, these data suggest that G724S is an allele-specific resistance mutation emerging in the context of Ex19Del but not L858R. Our results fundamentally reframe the problem of targeted therapy resistance from one focused on the "drug-resistance mutation" pair to one focused on the "activating mutation-drug-resistance mutation" trio. This has broad implications across clinical oncology.
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