ArticleCancer science2012
Hypoxia induces gefitinib resistance in non-small-cell lung cancer with both mutant and wild-type epidermal growth factor receptors.
Article in Cancer science, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 48 papers, 1 of them a synthesis that pooled it.
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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.
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Who cites it
48 citing papers in PubMed, 1 synthesis or guideline pooled it, 68 citations in OpenAlex.
- Clinicopathological and prognostic significance of hypoxia-inducible factor-1 alpha in lung cancer: a systematic review with meta-analysis.Journal of Huazhong University of Science and Technology. Medical sciences = Hua zhong ke ji da xue xue bao. Yi xue Ying De wen ban = Huazhong keji daxue xuebao. Yixue Yingdewen ban · 2016Pooled it
- Time-Resolved Network Entropy Analysis Identifies a CTNND1-VAV3 Subnetwork in Gefitinib-Resistant NSCLC.International journal of molecular sciences · 2026Article
- Interleukin-1α-Mediated Activation of TNF-α/NF-κB Signaling Confers Resistance to Osimertinib in EGFR-Mutant Non-Small-Cell Lung Cancer.Thoracic cancer · 2026Article
- FDX1 Regulates the Phosphorylation of ATM, DNA-PKcs Akt, and EGFR and Affects Radioresistance Under Severe Hypoxia in the Glioblastoma Cell Line T98G.International journal of molecular sciences · 2025Article
- Design and investigation of interactions of novel peptide conjugates of purine and pyrimidine derivatives with EGFR and its mutant T790M/L858R: an in silico and laboratory study.Molecular diversity · 2024Article
- Mechanisms of resistance to tyrosine kinase inhibitor-targeted therapy and overcoming strategies.MedComm · 2024Review
- Mechanistic prediction and validation of Brevilin A Therapeutic effects in Lung Cancer.BMC complementary medicine and therapies · 2024Article
- Evaluation of AMG510 Therapy onBioengineering (Basel, Switzerland) · 2022Article
- Novel Dimer Derivatives of PF-543 as Potential Antitumor Agents for the Treatment of Non-Small Cell Lung Cancer.Pharmaceutics · 2022Article
- Triple therapy with osimertinib, bevacizumab and cetuximab in EGFR-mutant lung cancer with HIF-1α/TGF-α expression.Oncology letters · 2021Article
- Review
- Hypoxia-InducedInternational journal of molecular sciences · 2021Article
- Quantitative Proteomic Approach Reveals Altered Metabolic Pathways in Response to the Inhibition of Lysine Deacetylases in A549 Cells under Normoxia and Hypoxia.International journal of molecular sciences · 2021Article
- Long non-coding RNAs in lung cancer: implications for lineage plasticity-mediated TKI resistance.Cellular and molecular life sciences : CMLS · 2021Review
- SIRT1/PGC-1α/PPAR-γ Correlate With Hypoxia-Induced Chemoresistance in Non-Small Cell Lung Cancer.Frontiers in oncology · 2021Review
- Nanomedicine of tyrosine kinase inhibitors.Theranostics · 2021Review
- PLGA Nanofiber/PDMS Microporous Composite Membrane-Sandwiched Microchip for Drug Testing.Micromachines · 2020Article
- Potential monoamine oxidase A inhibitor suppressing paclitaxel-resistant non-small cell lung cancer metastasis and growth.Thoracic cancer · 2020Article
- GLI1 activation is a key mechanism of erlotinib resistance in human non-small cell lung cancer.Oncology letters · 2020Article
- Targeting Hypoxia Sensitizes TNBC to Cisplatin and Promotes Inhibition of Both Bulk and Cancer Stem Cells.International journal of molecular sciences · 2020Article
Corrections and comments
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Authors and funding
13 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Somatic mutations in the epidermal growth factor receptor (EGFR) gene, such as exon 19 deletion mutations, are important factors in determining therapeutic responses to gefitinib in non-small-cell lung cancer (NSCLC). However, some patients have activating mutations in EGFR and show poor responses to gefitinib. In this study, we examined three NSCLC cell lines, HCC827, PC9, and HCC2935, that expressed an EGFR exon 19 deletion mutation. All cells expressed mutant EGFR, but the PC9 and HCC2935 cells also expressed wild-type EGFR. The HCC827 cells were highly sensitive to gefitinib under both normoxia and hypoxia. However, the PC9 and HCC2935 cells were more resistant to gefitinib under hypoxic conditions compared to normoxia. Phosphorylation of EGFR and ERK was suppressed with gefitinib treatment to a lesser extent under hypoxia. The expression of transforming growth factor-α (TGFα) was dramatically upregulated under hypoxia, and the knockdown of TGFα or hypoxia-inducible factor-1α (HIF1α) reversed the resistance to gefitinib in hypoxic PC9 and HCC2935 cells. Finally, introduction of the wild-type EGFR gene into the HCC827 cells caused resistance to gefitinib under hypoxia. This phenomenon was also reversed by the knockdown of TGFα or HIF1α. Our results indicate that hypoxia causes gefitinib resistance in EGFR-mutant NSCLC through the activation of wild-type EGFR mediated by the upregulation of TGFα. The presence of wild-type and mutant EGFR along with tumor hypoxia are important factors that should be considered when treating NSCLC patients with gefitinib.
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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.