ArticleJournal of the National Cancer Institute2013
Combating resistance to anti-IGFR antibody by targeting the integrin β3-Src pathway.
Article in Journal of the National Cancer Institute, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 45 citations in OpenAlex.
- The IGF Signalling Axis in Lung Cancer: Clinical Significance and Therapeutic Challenges.Journal of cellular and molecular medicine · 2025Article
- Targeting ITGβ3 to Overcome Trastuzumab Resistance through Epithelial-Mesenchymal Transition Regulation in HER2-Positive Breast Cancer.International journal of molecular sciences · 2024Article
- Overcoming Vemurafenib Resistance in Metastatic Melanoma: Targeting Integrins to Improve Treatment Efficacy.International journal of molecular sciences · 2024Article
- Inhibiting IGF1R-mediated Survival Signaling in Head and Neck Cancer with the Peptidomimetic SSTNCancer research communications · 2023Article
- Targeting MERTK and AXL inCancers · 2021Review
- IGF1R and Src inhibition induce synergistic cytotoxicity in HNSCC through inhibition of FAK.Scientific reports · 2021Article
- Development of the phenylpyrazolo[3,4-Theranostics · 2021Article
- Insulin-like growth factor receptor signaling in tumorigenesis and drug resistance: a challenge for cancer therapy.Journal of hematology & oncology · 2020Review
- Design, Synthesis, and Biological Evaluation of Proteolysis Targeting Chimeras (PROTACs) for the Dual Degradation of IGF-1R and Src.Molecules (Basel, Switzerland) · 2020Article
- Mechanisms of tRNA-derived fragments and tRNA halves in cancer treatment resistance.Biomarker research · 2020Review
- Suppression of Prostate Cancer Pathogenesis Using an MDA-9/Syntenin (SDCBP) PDZ1 Small-Molecule Inhibitor.Molecular cancer therapeutics · 2019Article
- Role of Integrins in Resistance to Therapies Targeting Growth Factor Receptors in Cancer.Cancers · 2019Review
- Development of a 4-aminopyrazolo[3,4-d]pyrimidine-based dual IGF1R/Src inhibitor as a novel anticancer agent with minimal toxicity.Molecular cancer · 2018Article
- Convergence of eicosanoid and integrin biology: Role of Src in 12-LOX activation.Experimental cell research · 2017Article
- Type I insulin-like growth factor receptor signaling in hematological malignancies.Oncotarget · 2017Review
- Loss of phosphodiesterase 4D mediates acquired triapine resistance via Epac-Rap1-Integrin signaling.Oncotarget · 2016Article
- IGF-1R and mTOR Blockade: Novel Resistance Mechanisms and Synergistic Drug Combinations for Ewing Sarcoma.Journal of the National Cancer Institute · 2016Article
- Essential role of insulin-like growth factor 2 in resistance to histone deacetylase inhibitors.Oncogene · 2016Article
- IGF-1R inhibition sensitizes breast cancer cells to ATM-related kinase (ATR) inhibitor and cisplatin.Oncotarget · 2016Article
- Article
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Authors and funding
11 authors at 2 institutions in 2 countries.
Funding
Abstract
backgroundSeveral phase II/III trials of anti-insulin-like growth factor 1 receptor (IGF-1R) monoclonal antibodies (mAbs) have shown limited efficacy. The mechanisms of resistance to IGF-1R mAb-based therapies and clinically applicable strategies for overcoming drug resistance are still undefined.
methodsIGF-1R mAb cixutumumab efficacy, alone or in combination with Src inhibitors, was evaluated in 10 human head and neck squamous cell carcinoma (HNSCC) and six non-small cell lung cancer (NSCLC) cell lines in vitro in two- or three-dimensional culture systems and in vivo in cell line- or patient-derived xenograft tumors in athymic nude mice (n = 6-9 per group). Cixutumumab-induced changes in cell signaling and IGF-1 binding to integrin β3 were determined by Western or ligand blotting, immunoprecipitation, immunofluorescence, and cell adhesion analyses and enzyme-linked immunosorbent assay. Data were analyzed by the two-sided Student t test or one-way analysis of variance.
resultsIntegrin β3-Src signaling cascade was activated by IGF-1 in HNSCC and NSCLC cells, when IGF-1 binding to IGF-1R was hampered by cixutumumab, resulting in Akt activation and cixutumumab resistance. Targeting integrin β3 or Src enhanced antitumor activity of cixutumumab in multiple cixutumumab-resistant cell lines and patient-derived tumors in vitro and in vivo. Mean tumor volume of mice cotreated with cixutumumab and integrin β3 siRNA was 133.7 mm(3) (95% confidence interval [CI] = 57.6 to 209.8 mm(3)) compared with those treated with cixutumumab (1472.5 mm(3); 95% CI = 1150.7 to 1794.3 mm(3); P < .001) or integrin β3 siRNA (903.2 mm(3); 95% CI = 636.1 to 1170.3 mm(3); P < .001) alone.
conclusionsIncreased Src activation through integrin ανβ3 confers considerable resistance against anti-IGF-1R mAb-based therapies in HNSCC and NSCLC cells. Dual targeting of the IGF-1R pathway and collateral integrin β3-Src signaling module may override this resistance.
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