ArticleThe Journal of clinical investigation2024
DNA topoisomerase II inhibition potentiates osimertinib's therapeutic efficacy in EGFR-mutant non-small cell lung cancer models.
Article in The Journal of clinical investigation, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed.
- Dual Targeting of DNA and EGFR by ZYH005 Induces DNA Damage and Mitotic Catastrophe in Glioblastoma.MedComm · 2026Article
- Cotargeting DNA topoisomerase II enhances efficacy of RAS-targeted therapy in KRAS-mutant cancer models.The Journal of clinical investigation · 2026Article
- Targeting Integrin β3: novel antiplatelet lignans 6'-Hydroxyjusticidin B and Neojusticin A from Justicia procumbens unveiled via multi-omics and biophysical validation.Natural products and bioprospecting · 2026Article
- Zeaxanthin targets TOP2A to regulate autophagy and suppress lung cancer progression via the MAPK/ERK pathway.Translational oncology · 2026Article
- Deciphering RNA and protein expression discordance identifies TOP2A as a prognostic biomarker and potential therapeutic target in lung adenocarcinoma.Discover oncology · 2026Article
- Targeting the E2F6-TOP2A-DKK1 axis: a novel therapeutic strategy for EMT-driven hepatocellular carcinoma progression.Frontiers in immunology · 2026Article
- Targeting MKK3/c-Myc interaction to overcome osimertinib acquired resistance in EGFR mutant lung cancer.Cancer letters · 2025Article
- Abietic Acid Induces DNA Damage and Cell Apoptosis in Lung Cancer Cells Through Targeting TOP2A.Biomolecules · 2025Article
- Exploring DNA topoisomerase II alpha in adrenocortical carcinoma through multi-omics analysis: a potential biomarker and therapeutic target.Acta biochimica et biophysica Sinica · 2025Article
- Article
- Roles and therapeutic opportunities of ω-3 long-chain polyunsaturated fatty acids in lung cancer.iScience · 2025Review
- HJURP modulates cell proliferation and chemoresistance via the MYC/TOP2A transcriptional axis in gastric cancer.Frontiers in molecular biosciences · 2025Article
- Knockdown of TOP2A reverses cisplatin resistance in ovarian cancer by inhibiting EMT via ferroptosis mediated by the TP53/GPX4/SLC7A11 axis.Frontiers in immunology · 2025Article
- Leveraging topoisomerase II-mediated DNA damage: repurposing etoposide as a lead compound for apicomplexan parasite control.Frontiers in veterinary science · 2025Article
- Targeting DNA Topoisomerase IIα in Retinoblastoma: Implications in EMT and Therapeutic Strategies.Biologics : targets & therapy · 2025Article
- Metabolic pathway activation and immune microenvironment features in non-small cell lung cancer: insights from single-cell transcriptomics.Frontiers in immunology · 2025Article
- Inhibition of hTERT/telomerase/telomere mediates therapeutic efficacy of osimertinib in EGFR mutant lung cancer.The Journal of experimental medicine · 2024Article
- Targeting Transient Receptor Potential Melastatin-2 (TRPM2) Enhances Therapeutic Efficacy of Third Generation EGFR Inhibitors against EGFR Mutant Lung Cancer.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
Corrections and comments
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Authors and funding
9 authors.
Funding
Abstract
Development of effective strategies to manage the inevitable acquired resistance to osimertinib, a third-generation EGFR inhibitor for the treatment of EGFR-mutant (EGFRm) non-small cell lung cancer (NSCLC), is urgently needed. This study reports that DNA topoisomerase II (Topo II) inhibitors, doxorubicin and etoposide, synergistically decreased cell survival, with enhanced induction of DNA damage and apoptosis in osimertinib-resistant cells; suppressed the growth of osimertinib-resistant tumors; and delayed the emergence of osimertinib-acquired resistance. Mechanistically, osimertinib decreased Topo IIα levels in EGFRm NSCLC cells by facilitating FBXW7-mediated proteasomal degradation, resulting in induction of DNA damage; these effects were lost in osimertinib-resistant cell lines that possess elevated levels of Topo IIα. Increased Topo IIα levels were also detected in the majority of tissue samples from patients with NSCLC after relapse from EGFR tyrosine kinase inhibitor treatment. Enforced expression of an ectopic TOP2A gene in sensitive EGFRm NSCLC cells conferred resistance to osimertinib, whereas knockdown of TOP2A in osimertinib-resistant cell lines restored their susceptibility to osimertinib-induced DNA damage and apoptosis. Together, these results reveal an essential role of Topo IIα inhibition in mediating the therapeutic efficacy of osimertinib against EGFRm NSCLC, providing scientific rationale for targeting Topo II to manage acquired resistance to osimertinib.
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