ArticleMolecular cancer research : MCR2010
Cancer-associated fibroblasts derived from EGFR-TKI-resistant tumors reverse EGFR pathway inhibition by EGFR-TKIs.
Article in Molecular cancer research : MCR, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers.
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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
45 citing papers in PubMed, 82 citations in OpenAlex.
- Decoding the role of cancer-associated fibroblasts in cisplatin resistance of head and neck squamous cell carcinoma.iScience · 2026Review
- Shaping the battlefield: EGFR and KRAS tumor mutations' role on the immune microenvironment and immunotherapy responses in lung cancer.Cancer metastasis reviews · 2025Review
- Single-Cell RNA Sequencing in Unraveling Acquired Resistance to EGFR-TKIs in Non-Small Cell Lung Cancer: New Perspectives.International journal of molecular sciences · 2025Review
- Article
- Adipocyte Precursor-Derived NRG1 Promotes Resistance to FGFR Inhibition in Urothelial Carcinoma.Cancer research · 2024Article
- An atlas of cell-type-specific interactome networks across 44 human tumor types.Genome medicine · 2024Article
- Decoding tumor-fibrosis interplay: mechanisms, impact on progression, and innovative therapeutic strategies.Frontiers in pharmacology · 2024Review
- Research Progress on Therapeutic Targeting of Cancer-Associated Fibroblasts to Tackle Treatment-Resistant NSCLC.Pharmaceuticals (Basel, Switzerland) · 2022Review
- Construction and Verification of a Fibroblast-Related Prognostic Signature Model for Colon Cancer.Frontiers in genetics · 2022Article
- Review
- Signaling pathways in cancer-associated fibroblasts and targeted therapy for cancer.Signal transduction and targeted therapy · 2021Review
- Research advances of secretory proteins in malignant tumors.Chinese journal of cancer research = Chung-kuo yen cheng yen chiu · 2021Article
- The Interaction Between Long Non-Coding RNAs and Cancer-Associated Fibroblasts in Lung Cancer.Frontiers in cell and developmental biology · 2021Review
- Emergence of Cancer-Associated Fibroblasts as an Indispensable Cellular Player in Bone Metastasis Process.Cancers · 2020Review
- Review
- Characterization and printability of Sodium alginate -Gelatin hydrogel for bioprinting NSCLC co-culture.Scientific reports · 2019Article
- Activated Fibroblast Program Orchestrates Tumor Initiation and Progression; Molecular Mechanisms and the Associated Therapeutic Strategies.International journal of molecular sciences · 2019Review
- The effects and the mechanisms of autophagy on the cancer-associated fibroblasts in cancer.Journal of experimental & clinical cancer research : CR · 2019Review
- A novel ligand-receptor relationship between families of ribonucleases and receptor tyrosine kinases.Journal of biomedical science · 2018Review
- TGF-β and the Tissue Microenvironment: Relevance in Fibrosis and Cancer.International journal of molecular sciences · 2018Review
Corrections and comments
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
Epidermal growth factor receptor (EGFR) plays a critical role in oncogenesis, which makes it an attractive target for pharmacologic inhibition. Yet, EGFR inhibition with tyrosine kinase inhibitors (TKI) does not result in a measurable and sustainable clinical benefit in a vast majority of tumors. This emphasizes the need for further investigations into resistance mechanisms against EGFR-TKIs. We previously reported the generation of an in vivo adenocarcinoma model of EGFR-TKI-acquired resistance that was devoid of the known mechanisms of resistance. Using this same xenograft model, we now show that the tumor stroma plays an important role in limiting responsiveness to EGFR-TKIs. EGFR-TKI-resistant tumors display increased surface expression of CD44(hi)/CD24(lo) and markers of epithelial to mesenchymal transition (EMT), SNAI1, and N-cadherin. An in vivo green fluorescent protein-tagging approach reveals that the tumor stroma of the EGFR-TKI-resistant tumors is distinct in that 24% of its cancer-associated fibroblast (CAF) population is composed of EMT-derived tumor cells that represent the in vivo escape from EGFR-TKIs. We further show that EMT subpopulation-harboring CAFs isolated from the EGFR-TKI-resistant tumors are tumorigenic and express the biomarker of gefitinib resistance, epithelial membrane protein-1. Finally, we provide evidence that paracrine factors secreted from the EGFR-TKI-resistant CAFs mitigate the EGFR-TKI-mediated blockade of pEGFR and pMAPK in cocultured tumor cells, regardless of their EGFR mutational status. This is the first demonstration that the tumor stroma is modified with acquisition of EGFR-TKI resistance and that it further contributes in promoting drug resistance.
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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.