ArticleThe Journal of clinical investigation2008
Acquired resistance to EGFR tyrosine kinase inhibitors in cancer cells is mediated by loss of IGF-binding proteins.
Article in The Journal of clinical investigation, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 275 papers, 2 of them syntheses that pooled it.
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The trial behind it
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.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
275 citing papers in PubMed, 2 syntheses or guidelines pooled it, 522 citations in OpenAlex.
- Dual inhibiting EGFR and VEGF pathways versus EGFR-TKIs alone in the treatment of advanced non-small-cell lung cancer: a meta-analysis of randomized controlled trials.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2016Pooled it
- Comparison of the efficacy and safety of single-agent erlotinib and doublet molecular targeted agents based on erlotinib in advanced non-small cell lung cancer (NSCLC): a systematic review and meta-analysis.Targeted oncology · 2013Pooled it
- Randomised Phase 2 study of maintenance linsitinib (OSI-906) in combination with erlotinib compared with placebo plus erlotinib after platinum-based chemotherapy in patients with advanced non-small cell lung cancer.British journal of cancer · 2017Trial
- Single nucleotide polymorphisms in the IGF-IRS pathway are associated with outcome in mCRC patients enrolled in the FIRE-3 trial.International journal of cancer · 2017Trial
- Anticancer activity of the type I insulin-like growth factor receptor antagonist, ganitumab, in combination with the death receptor 5 agonist, conatumumab.Targeted oncology · 2015Trial
- Trial
- A phase I/II study of erlotinib in combination with the anti-insulin-like growth factor-1 receptor monoclonal antibody IMC-A12 (cixutumumab) in patients with advanced non-small cell lung cancer.Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer · 2012Trial
- Randomized phase II study of erlotinib in combination with placebo or R1507, a monoclonal antibody to insulin-like growth factor-1 receptor, for advanced-stage non-small-cell lung cancer.Journal of clinical oncology : official journal of the American Society of Clinical Oncology · 2011Trial
- Insulin-like growth factor receptor signaling in physiology and disease.Signal transduction and targeted therapy · 2026Review
- Inhibition of SHP2 enhances the effects of selective receptor tyrosine kinase inhibitors in untreated preclinical models of RET-mutated thyroid cancer.Investigational new drugs · 2026Article
- The resistance landscape of EGFR tyrosine kinase inhibitors in advanced non-small cell lung cancer: molecular mechanisms and novel therapeutic strategies.Translational lung cancer research · 2026Review
- Drug-Tolerant Persister Cells and Tumor Dormancy in NSCLC: A New Frontier in Overcoming Therapeutic Resistance.Cancers · 2026Review
- IGF-1R inhibitors in cancer: A review of available evidence and future outlook.Critical reviews in oncology/hematology · 2025Review
- Intracellular cholesterol: new functions and therapeutic approaches in NSCLC EGFR-TKI resistance.Lipids in health and disease · 2025Review
- An "AND" logic gate-based supramolecular therapeutic nanoplatform for combatting drug-resistant non-small cell lung cancer.Science advances · 2024Article
- The Evolving Paradigm of Antibody-Drug Conjugates Targeting the ErbB/HER Family of Receptor Tyrosine Kinases.Pharmaceutics · 2024Review
- Identification of New Chemoresistance-Associated Genes in Triple-Negative Breast Cancer by Single-Cell Transcriptomic Analysis.International journal of molecular sciences · 2024Article
- Activation of IGFBP4 via unconventional mechanism of miRNA attenuates metastasis of intrahepatic cholangiocarcinoma.Hepatology international · 2024Article
- Research progress on the role of bypass activation mechanisms in resistance to tyrosine kinase inhibitors in non-small cell lung cancer.Frontiers in oncology · 2024Review
- Multi-kinase compensation rescues EGFR knockout in a cell line model of head and neck squamous cell carcinoma.Archives of oral biology · 2023Article
215 more citing papers are in PubMed but not listed here.
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Authors and funding
11 authors at 4 institutions in 1 country.
Funding
Abstract
Although some cancers are initially sensitive to EGFR tyrosine kinase inhibitors (TKIs), resistance invariably develops. We investigated mechanisms of acquired resistance to the EGFR TKI gefitinib by generating gefitinib-resistant (GR) A431 squamous cancer cells. In GR cells, gefitinib reduced phosphorylation of EGFR, ErbB-3, and Erk but not Akt. These cells also showed hyperphosphorylation of the IGFI receptor (IGFIR) and constitutive association of IRS-1 with PI3K. Inhibition of IGFIR signaling disrupted the association of IRS-1 with PI3K and restored the ability of gefitinib to downregulate PI3K/Akt signaling and to inhibit GR cell growth. Gene expression analyses revealed that GR cells exhibited markedly reduced IGF-binding protein 3 (IGFBP-3) and IGFBP-4 RNA. Addition of recombinant IGFBP-3 restored the ability of gefitinib to downregulate PI3K/Akt signaling and to inhibit cell growth. Finally, gefitinib treatment of mice with A431 xenografts in combination with an IGFIR-specific monoclonal antibody prevented tumor recurrence, whereas each drug given alone was unable to do so. These data suggest that loss of expression of IGFBPs in tumor cells treated with EGFR TKIs derepresses IGFIR signaling, which in turn mediates resistance to EGFR antagonists. Moreover, combined therapeutic inhibition of EGFR and IGFIR may abrogate this acquired mechanism of drug resistance and is thus worthy of prospective clinical investigation.
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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.