ArticleCancer research2020
Hypoxia Induces Resistance to EGFR Inhibitors in Lung Cancer Cells via Upregulation of FGFR1 and the MAPK Pathway.
Article in Cancer research, 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, 114 citations in OpenAlex.
- Time-Resolved Network Entropy Analysis Identifies a CTNND1-VAV3 Subnetwork in Gefitinib-Resistant NSCLC.International journal of molecular sciences · 2026Article
- Multiprotein-based nanomedicines with dual CD44/CD133 targeting and GSH-responsive drug release for improving cancer chemotherapy.Drug delivery and translational research · 2026Article
- Stress-responsive membrane proteins as execution nodes of tumor cell adaptation to microenvironmental stress.Oncogene · 2026Review
- Targeting PLK1 potentiates the antitumor efficacy of EGFR-TKIs through inhibiting the JAK1/STAT3 pathway.Cell death & disease · 2026Article
- Traditional Chinese medicine reprograms the tumor microenvironment to overcome EGFR-TKI resistance: mechanisms and therapeutic perspectives.Frontiers in pharmacology · 2026Review
- Next Generation DNA Damage Response Inhibitors: Harnessing Nanocarriers and Tumor Microenvironment for Precision Cancer Therapy.Oncology research · 2026Review
- Advances in understanding the mechanisms underlying acquired resistance to third-generation tyrosine kinase inhibitors in non-small cell lung cancer.Frontiers in cell and developmental biology · 2026Review
- Encoding functional edges in graphs to model spatially varying relationships in the tumor microenvironment.NPJ artificial intelligence · 2026Article
- REDD1 Affects Proliferation, Apoptosis, Migration, and Colony Formation via p-ERK and p-JNK Signaling in Lung Adenocarcinoma Cells Under Hypoxia.Biomedicines · 2025Article
- EGFR Targeted Liposomal PROTAC Assisted With Epigenetic Regulation as an Efficient Strategy for Osimertinib-Resistant Lung Cancer Therapy.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Epigenetic modification of cuproptosis by non-coding RNAs in cancer drug resistance.Molecular cancer · 2025Review
- EGFR mutations in non-small cell lung cancer: Classification, characteristics and resistance to third-generation EGFR-tyrosine kinase inhibitors (Review).Oncology letters · 2025Review
- Hypoxia-inducible APCDD1L-AS1 promotes osimertinib resistance by stabilising DLST to drive tricarboxylic acid cycle in lung adenocarcinoma.Journal of experimental & clinical cancer research : CR · 2025Article
- Strategies to Overcome Resistance to Osimertinib in EGFR-Mutated Lung Cancer.International journal of molecular sciences · 2025Review
- Unraveling the triad of hypoxia, cancer cell stemness, and drug resistance.Journal of hematology & oncology · 2025Review
- Canonical and noncanonical NOTCH signaling in the nongenetic resistance of cancer: distinct and concerted control.Frontiers of medicine · 2025Review
- Optimizing Osimertinib for NSCLC: Targeting Resistance and Exploring Combination Therapeutics.Cancers · 2025Review
- Review
- SLC16A3 drives lung adenocarcinoma progression and gefitinib resistance through coordinated regulation of ferroptosis and lactate metabolism.Frontiers in immunology · 2025Article
- TFAP2A drives non-small cell lung cancer (NSCLC) progression and resistance to targeted therapy by facilitating the ESR2-mediated MAPK pathway.Cell death discovery · 2024Article
Corrections and comments
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Authors and funding
6 authors at 3 institutions in 2 countries.
Funding
Abstract
Development of resistance remains the key obstacle to the clinical efficacy of EGFR tyrosine kinase inhibitors (TKI). Hypoxia is a key microenvironmental stress in solid tumors associated with acquired resistance to conventional therapy. Consistent with our previous studies, we show here that long-term, moderate hypoxia promotes resistance to the EGFR TKI osimertinib (AZD9291) in the non-small cell lung cancer (NSCLC) cell line H1975, which harbors two EGFR mutations including T790M. Hypoxia-induced resistance was associated with development of epithelial-mesenchymal transition (EMT) coordinated by increased expression of ZEB-1, an EMT activator. Hypoxia induced increased fibroblast growth factor receptor 1 (FGFR1) expression in NSCLC cell lines H1975, HCC827, and YLR086, and knockdown of FGFR1 attenuated hypoxia-induced EGFR TKI resistance in each line. Upregulated expression of FGFR1 by hypoxia was mediated through the MAPK pathway and attenuated induction of the proapoptotic factor BIM. Consistent with this, inhibition of FGFR1 function by the selective small-molecule inhibitor BGJ398 enhanced EGFR TKI sensitivity and promoted upregulation of BIM levels. Furthermore, inhibition of MEK activity by trametinib showed similar effects. In tumor xenografts in mice, treatment with either BGJ398 or trametinib enhanced response to AZD9291 and improved survival. These results suggest that hypoxia is a driving force for acquired resistance to EGFR TKIs through increased expression of FGFR1. The combination of EGFR TKI and FGFR1 or MEK inhibitors may offer an attractive therapeutic strategy for NSCLC. SIGNIFICANCE: Hypoxia-induced resistance to EGFR TKI is driven by overexpression of FGFR1 to sustain ERK signaling, where a subsequent combination of EGFR TKI with FGFR1 inhibitors or MEK inhibitors reverses this resistance. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/21/4655/F1.large.jpg.
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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.