ArticleJournal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer2020
Exon 16-Skipping HER2 as a Novel Mechanism of Osimertinib Resistance in EGFR L858R/T790M-Positive Non-Small Cell Lung Cancer.
Article in Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 55 papers.
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Who cites it
55 citing papers in PubMed, 82 citations in OpenAlex.
- Observational
- A Non-Canonical Core Transcriptional Regulatory Circuit Orchestrates Chromatin Reprogramming to Drive Osimertinib Resistance in Non-Small Cell Lung Cancer.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- HER2∆16 directs luminal cell identity and estrogen receptor signaling in HER2+ breast cancer.Nature communications · 2026Article
- Charting the blueprint: a bibliometric analysis reveals future strategies in lung cancer targeted therapy (2003-2025).Journal of thoracic disease · 2026Article
- Mechanisms of acquired resistance to osimertinib in EGFR T790M-Positive lung adenocarcinoma.Frontiers in genetics · 2026Article
- PD-L1 regulates c-MET phosphorylation and contributes to MET-dependent resistance to osimertinib in EGFR-mutant NSCLC.Journal of biomedical science · 2025Article
- 5-HT regulates resistance to aumolertinib by attenuating ferroptosis in lung adenocarcinoma.EMBO molecular medicine · 2025Article
- Alternative Splicing in Tumorigenesis and Cancer Therapy.Biomolecules · 2025Review
- Risk factors for radiation pneumonitis in NSCLC patients treated with third-generation EGFR TKIs and chest radiotherapy.Radiation oncology (London, England) · 2025Article
- RNA splicing: Novel star in pulmonary diseases with a treatment perspective.Acta pharmaceutica Sinica. B · 2025Review
- Review
- Diverse ERBB2/ERBB3 Activating Alterations and Coalterations Have Implications for HER2/3-Targeted Therapies across Solid Tumors.Cancer research communications · 2025Article
- Strategies to Overcome Resistance to Osimertinib in EGFR-Mutated Lung Cancer.International journal of molecular sciences · 2025Review
- Piperlongumine overcomes osimertinib resistance via governing ubiquitination-modulated Sp1 turnover.JCI insight · 2025Article
- Possibilities of Overcoming Resistance to Osimertinib in NSCLC Patients with Mutations in theCancers · 2025Review
- Optimizing Osimertinib for NSCLC: Targeting Resistance and Exploring Combination Therapeutics.Cancers · 2025Review
- Targeting RTKs/nRTKs as promising therapeutic strategies for the treatment of triple-negative breast cancer: evidence from clinical trials.Military Medical Research · 2024Review
- New clinical trial design in precision medicine: discovery, development and direction.Signal transduction and targeted therapy · 2024Review
- Mechanisms of resistance to targeted therapy and immunotherapy in non-small cell lung cancer: promising strategies to overcoming challenges.Frontiers in immunology · 2024Review
- SIRT6 promotes metastasis and relapse in HER2-positive breast cancer.Scientific reports · 2023Article
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Authors and funding
7 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
introductionOsimertinib is the current recommended treatment for EGFR T790M-positive NSCLC after EGFR tyrosine kinase inhibitor therapy. However, resistance to osimertinib therapy is inevitably acquired after a period of effective treatment. We had a patient with EGFR L858R/T790M-positive NSCLC who initially responded to osimertinib therapy but eventually experienced development of resistance. Plasma cell-free DNA analysis revealed the occurrence of exon 16-skipping HER2, which may have resulted in the erb-b2 receptor tyrosine kinase 2 gene (HER2) splice variant HER2D16. HER2D16 has never been reported in lung cancer, and HER2D16-driven signaling is known to be regulated by Src kinase in breast cancer. We investigated the role of HER2D16 as an osimertinib-resistant mechanism.
methodsWe constructed and established H1975 cells stably expressing HER2D16. The dimeric formation of HER2D16 was tested by using nonreducing polyacrylamide gel electrophoresis. The effects of the study drugs on signaling transduction were examined by using Western blot. Synergistic effect was assessed by using the Chou-Talalay method.
resultsWe found that HER2D16 can form a homodimer in NSCLC cells. HER2D16-expressing H1975 cells were resistant to osimertinib treatment. We also found that mutant EGFR and HER2D16 cooperated to activate downstream signaling for osimertinib resistance. In addition, cotreatment with osimertinib and an Src kinase inhibitor failed to reverse resistance, indicating that HER2D16-driven signaling in NSCLC did not occur through a canonical pathway. Finally, we revealed that the combination of osimertinib with the pan-HER small-molecule inhibitor afatinib could synergistically repress cell growth and signaling in H1975-HER2D16 cells.
conclusionHER2D16 can contribute to osimertinib resistance through an Src-independent pathway. HER2D16 should be included in the molecular diagnosis panel for lung cancer.
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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.