Combating Resistance to Anti-IGFR Antibody by Targeting the Integrin β3-Src Pathway

• Published in: JNCI : Journal of the National Cancer Institute 2013-10, Vol.105 (20), p.1558-1570
• Main Authors: DONG HOON SHIN, LEE, Hyo-Jong, LEE, Ho-Young, MIN, Hye-Young, SUN PHIL CHOI, LEE, Mi-Sook, JUNG WEON LEE, JOHNSON, Faye M, MEHTA, Kapil, LIPPMAN, Scott M, GLISSON, Bonnie S
• Format: Article
• Language: English
• Subjects: Analysis of Variance; Animals; Antibodies, Monoclonal - pharmacology; Antibodies, Monoclonal, Humanized; Antineoplastic Agents - pharmacology; Biological and medical sciences; Blotting, Western; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Squamous Cell - drug therapy; Carcinoma, Squamous Cell - metabolism; CSK Tyrosine-Protein Kinase; Drug Resistance, Neoplasm - drug effects; Enzyme-Linked Immunosorbent Assay; Fluorescent Antibody Technique; Head and Neck Neoplasms - drug therapy; Head and Neck Neoplasms - metabolism; Humans; Immunoprecipitation; Integrin beta3 - pharmacology; Lung Neoplasms - drug therapy; Medical sciences; Mice; Mice, Nude; Phosphorylation - drug effects; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins c-akt - drug effects; Proto-Oncogene Proteins c-akt - metabolism; Receptor, IGF Type 1 - immunology; Signal Transduction - drug effects; Squamous Cell Carcinoma of Head and Neck; src-Family Kinases - antagonists & inhibitors; Tumors; Xenograft Model Antitumor Assays
• ISSN: 0027-8874; 1460-2105
• DOI: 10.1093/jnci/djt263

Several 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. IGF-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. Integrin 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. Increased 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.