ArticleTargeted oncology2019
Acquired BRAF G469A Mutation as a Resistance Mechanism to First-Line Osimertinib Treatment in NSCLC Cell Lines Harboring an EGFR Exon 19 Deletion.
Article in Targeted oncology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed.
- Leveraging Acquired EGFR-TKI-Resistant Models to Identify MUC16 as a Therapeutic Vulnerability in Lung Adenocarcinoma.Pharmaceuticals (Basel, Switzerland) · 2025Article
- Analysis of genomic alternations in epidermal growth factor receptor (EGFR)-T790M-mutated non-small cell lung cancer (NSCLC) patients with acquired resistance to osimertinib therapy.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2025Article
- Combined BRAF G469A mutation and echinoderm microtubule associated protein like-4-anaplastic lymphoma kinase rearrangement with resistance: A case report and review of literature.World journal of clinical oncology · 2025Article
- Optimizing Osimertinib for NSCLC: Targeting Resistance and Exploring Combination Therapeutics.Cancers · 2025Review
- EGFR inhibitors plus dabrafenib and trametinib in patients with EGFR-mutant lung cancer and resistance mediated by BRAFTranslational lung cancer research · 2024Article
- Personalizing Therapy Outcomes through Mitogen-Activated Protein Kinase Pathway Inhibition in Non-Small Cell Lung Cancer.Biomedicines · 2024Review
- Targeting glucosylceramide synthase induces antiproliferative and proapoptotic effects in osimertinib-resistant NSCLC cell models.Scientific reports · 2024Article
- Research progress on the role of bypass activation mechanisms in resistance to tyrosine kinase inhibitors in non-small cell lung cancer.Frontiers in oncology · 2024Review
- Mechanisms of resistance to targeted therapy and immunotherapy in non-small cell lung cancer: promising strategies to overcoming challenges.Frontiers in immunology · 2024Review
- Intrinsic Resistance to Osimertinib in EGFR Mutated NSCLC Cell Lines Induced by Alteration in Cell-Cycle Regulators.Targeted oncology · 2023Article
- Therapeutic strategies for EGFR-mutated non-small cell lung cancer patients with osimertinib resistance.Journal of hematology & oncology · 2022Review
- Fasudil Increased the Sensitivity to Gefitinib in NSCLC by Decreasing Intracellular Lipid Accumulation.Cancers · 2022Article
- Characteristics of and Treatment Strategies for AdvancedJTO clinical and research reports · 2022Article
- Review
- The Evolution of BRAF Activation in Non-Small-Cell Lung Cancer.Frontiers in oncology · 2022Review
- Preclinical Models for Acquired Resistance to Third-Generation EGFR Inhibitors in NSCLC: Functional Studies and Drug Combinations Used to Overcome Resistance.Frontiers in oncology · 2022Review
- TargetingPharmaceutics · 2021Review
- Review
- Managing Acquired Resistance to Third-Generation EGFR Tyrosine Kinase Inhibitors Through Co-Targeting MEK/ERK Signaling.Lung Cancer (Auckland, N.Z.) · 2021Review
- Article
Corrections and comments
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Authors and funding
12 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundOsimertinib is a new third-generation, epidermal growth factor receptor-tyrosine kinase inhibitor highly selective for the epidermal growth factor receptor with both activating and T790M mutations. A recent phase III trial showed a statistically significant progression-free survival benefit with osimertinib vs. gefitinib or erlotinib as first-line treatment for EGFR-mutated non-small cell lung cancer, and preliminary data are available on resistance mechanisms to first-line osimertinib therapy.
objectiveThe objective of this study was to examine potential in vitro mechanisms of acquired resistance to osimertinib in a cell model carrying an EGFR exon 19 deletion.
methodsPC9 cells were cultured in the presence of increasing concentrations of osimertinib (ranging from 10 to 500 nM) to generate resistant cells. Three clones resistant to osimertinib (half maximal inhibitory concentration > 1 μM) were isolated, genotyped by next-generation sequencing and tested for drug sensitivity. Cell proliferation and migration, cell death, and signaling transduction pathways were analyzed.
resultsOur study revealed that all the three resistant clones developed acquired resistance via the BRAF G469A mutation maintaining a constitutive activation of the ERK pathway. Stable transfection of PC9 and HCC827 cells with a plasmid containing BRAF G469A rendered the cells resistant to osimertinib. Treatment with selumetinib and trametinib, but not dabrafenib, restored the sensitivity to osimertinib and enhanced cell death in the resistant clones with the BRAF G469A mutation.
conclusionsOur in vitro studies revealed the BRAF G469A-activating mutation as a potential mechanism of acquired resistance to first-line osimertinib treatment, and provide a strategy of intervention to overcome this mechanism of resistance.
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Registered trials
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