ArticleClinical cancer research : an official journal of the American Association for Cancer Research2016
InsR/IGF1R Pathway Mediates Resistance to EGFR Inhibitors in Glioblastoma.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 53 papers.
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Who cites it
53 citing papers in PubMed, 79 citations in OpenAlex.
- Overcoming IGF1R-mediated resistance to oncolytic HSV1 and radiotherapy via triple combination therapy.Cell death & disease · 2026Article
- A novel quinazolinone insulin receptor inhibitor and its synergy with an EGFR inhibitor in glucose-driven glioblastoma.Molecular oncology · 2026Article
- Redundancy in Growth Factor Receptor Signaling in Adult Astrocytoma Resistance to Small-Molecule Tyrosine Kinase Inhibitors.International journal of molecular sciences · 2026Review
- Overcoming IGF1R-Mediated Resistance to Oncolytic HSV1 and Radiotherapy via Triple Combination Therapy.Research square · 2025Article
- Identification of endothelial INSR as an osteosarcoma-related biomarker and therapeutic target based on weighted gene co-expression network analysis.Discover oncology · 2025Article
- Multiscale mathematical model-informed reinforcement learning optimizes combination treatment scheduling in glioblastoma evolution.Science advances · 2025Article
- Nanoparticle encapsulation enables systemic IGF-Trap delivery to inhibit intracerebral glioma growth.Neuro-oncology · 2025Article
- Kinase-Targeted Therapies for Glioblastoma.International journal of molecular sciences · 2025Review
- Transcranial Magnetic Stimulation Enhances the Therapeutic Effect of IGF-Trap in Intracerebral Glioma Models.Pharmaceuticals (Basel, Switzerland) · 2024Article
- Receptor Pharmacogenomics: Deciphering Genetic Influence on Drug Response.International journal of molecular sciences · 2024Review
- Inhibition of EGFR Pathway Suppresses M1 Macrophage Polarization and Osteoclastogenesis, Mitigating Titanium Particle-Induced Bone Resorption.Journal of inflammation research · 2024Article
- Costs and Causes of Oncology Drug Attrition With the Example of Insulin-Like Growth Factor-1 Receptor Inhibitors.JAMA network open · 2023Article
- Protein tyrosine kinase inhibitor resistance in malignant tumors: molecular mechanisms and future perspective.Signal transduction and targeted therapy · 2022Review
- IGF-binding proteins secreted by cancer-associated fibroblasts induce context-dependent drug sensitization of lung cancer cells.Science signaling · 2022Article
- GZ17-6.02 Inhibits the Growth of EGFRvIII+ Glioblastoma.International journal of molecular sciences · 2022Article
- The Induced Expression ofInternational journal of molecular sciences · 2022Article
- Advancements, Challenges, and Future Directions in Tackling Glioblastoma Resistance to Small Kinase Inhibitors.Cancers · 2022Review
- Anoikis resistance in diffuse glioma: The potential therapeutic targets in the future.Frontiers in oncology · 2022Review
- An insulin growth factor-I/II-neutralizing monoclonal antibody in combination with epidermal growth factor receptor inhibitors potently inhibits tumor cell growth.Journal of Cancer · 2022Article
- Review
Corrections and comments
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Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
Abstract
purposeAberrant activation of EGFR is a hallmark of glioblastoma. However, EGFR inhibitors exhibit at best modest efficacy in glioblastoma. This is in sharp contrast with the observations in EGFR-mutant lung cancer. We examined whether activation of functionally redundant receptor tyrosine kinases (RTKs) conferred resistance to EGFR inhibitors in glioblastoma. EXPERIMENTAL
designWe collected a panel of patient-derived glioblastoma xenograft (PDX) lines that maintained expression of wild-type or mutant EGFR in serial xenotransplantation and tissue cultures. Using this physiologically relevant platform, we tested the abilities of several RTK ligands to protect glioblastoma cells against an EGFR inhibitor, gefitinib. Based on the screening results, we further developed a combination therapy cotargeting EGFR and insulin receptor (InsR)/insulin-like growth factor 1 receptor (IGF1R).
resultsInsulin and IGF1 induced significant protection against gefitinib in the majority of EGFR-dependent PDX lines with one exception that did not express InsR or IGF1R. Blockade of the InsR/IGF1R pathway synergistically improved sensitivity to gefitinib or dacomitinib. Gefitinib alone effectively attenuated EGFR activities and the downstream MEK/ERK pathway. However, repression of AKT and induction of apoptosis required concurrent inhibition of both EGFR and InsR/IGF1R. A combination of gefitinib and OSI-906, a dual InsR/IGF1R inhibitor, was more effective than either agent alone to treat subcutaneous glioblastoma xenograft tumors.
conclusionsOur results suggest that activation of the InsR/IGF1R pathway confers resistance to EGFR inhibitors in EGFR-dependent glioblastoma through AKT regulation. Concurrent blockade of these two pathways holds promise to treat EGFR-dependent glioblastoma.
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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.