Inhibition of EGFR or IGF‐1R signaling enhances radiation response in head and neck cancer models but concurrent inhibition has no added benefit

• Published in: Cancer medicine (Malden, MA) MA), 2015-01, Vol.4 (1), p.65-74
• Main Authors: Raju, Uma, Molkentine, David P., Valdecanas, David R., Deorukhkar, Amit, Mason, Kathryn A., Buchholz, Thomas A., Meyn, Raymond E., Ang, Kie‐Kian, Skinner, Heath
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Monoclonal, Humanized - pharmacology; Antineoplastic Agents - pharmacology; Cancer Research; Cancer therapies; Cell Line, Tumor; Cell survival; Cell Survival - drug effects; Cell viability; Cetuximab; Chemotherapy; Cytotoxicity; Disease Models, Animal; DNA Breaks, Double-Stranded - drug effects; DNA Breaks, Double-Stranded - radiation effects; DNA repair; Drug dosages; Epidermal growth factor; Epidermal growth factor receptors; ErbB Receptors - genetics; ErbB Receptors - metabolism; Gene Expression; Growth factors; Head & neck cancer; Head and Neck Neoplasms - genetics; Head and Neck Neoplasms - metabolism; Head and Neck Neoplasms - mortality; Head and Neck Neoplasms - pathology; Head and Neck Neoplasms - therapy; Head and neck squamous cell carcinoma; Histones - metabolism; Humans; IGF‐1R and EGFR signaling; Immunofluorescence; Immunoglobulins; Insulin; Insulin-like growth factors; Intracellular Signaling Peptides and Proteins - metabolism; Monoclonal antibodies; Protein Multimerization - drug effects; Proteins; Radiation; Radiation therapy; Radiation Tolerance - drug effects; Radiosensitivity; Radiotherapy; Receptor, IGF Type 1 - genetics; Receptor, IGF Type 1 - metabolism; Signal Transduction - drug effects; Software; Squamous cell carcinoma; Targeted cancer therapy; Tumor Burden - drug effects; Tumor Burden - radiation effects; tumor response to radiation; Tumor Suppressor p53-Binding Protein 1; Tumors; Western blotting; Xenograft Model Antitumor Assays; Xenografts
• ISSN: 2045-7634; 2045-7634
• DOI: 10.1002/cam4.345

Interaction between the epidermal growth factor receptor (EGFR) and the insulin‐like growth factor receptor (IGF‐1R) has been well established in many cancer types. We investigated the effects of cetuximab (EGFR antibody) and IMC‐A12 (IGF‐1R antibody) on the response of head and neck squamous cell carcinoma (HNSCC) to radiation therapy (RT). The effects of cetuximab and IMC‐A12 on cell viability and radiosensitivity were determined by clonogenic cell survival assay. Formation of nuclear γ‐H2AX and 53BP1 foci was monitored by immunofluorescence. Alterations in target signaling were analyzed by Western blots. In vivo tumor growth delay assay was performed to determine the efficacy of triple therapy with IMC‐A12, cetuximab, and RT. In vitro data showed that cetuximab differentially affected the survival and the radiosensitivity of HNSCC cells. Cetuximab suppressed DNA repair that was evident by the prolonged presence of nuclear γ‐H2AX and 53BP1 foci. IMC‐A12 did not have any effect on the cell survival. However, it increased the radiosensitivity of one of the cell lines. EGFR inhibition increased IGF‐1R expression levels and also the association between EGFR and IGF‐1R. Addition of IMC‐A12 to cetuximab did not increase the radiosensitivity of these cells. Tumor xenografts exhibited enhanced response to RT in the presence of either cetuximab or IMC‐A12. Concurrent treatment regimen failed to further enhance the tumor response to cetuximab and/or RT. Taken together our data suggest that concomitant inhibition of both EGFR and IGF‐1R pathways did not yield additional therapeutic benefit in overcoming resistance to RT. We investigated the effects of cetuximab (epidermal growth factor receptor; EGFR antibody) and IMC‐A12 (insulin‐like growth factor receptor; IGF‐1R antibody) on the response of head and neck squamous cell carcinoma (HNSCC) to radiation therapy (RT). Our data suggest that concomitant inhibition of both EGFR and IGF‐1R pathways did not yield additional therapeutic benefit in overcoming resistance to RT.