title: Inhibition of EGFR or IGF-1R signaling enhances radiation response in head and neck cancer models but concurrent inhibition has no added benefit.
abstract: 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.
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Uma
authors.initials: U
authors.lastname: Raju
authors.forename: David P
authors.initials: DP
authors.lastname: Molkentine
authors.forename: David R
authors.initials: DR
authors.lastname: Valdecanas
authors.forename: Amit
authors.initials: A
authors.lastname: Deorukhkar
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Mason
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Buchholz
authors.forename: Raymond E
authors.initials: RE
authors.lastname: Meyn
authors.forename: Kie-Kian
authors.initials: KK
authors.lastname: Ang
authors.forename: Heath
authors.initials: H
authors.lastname: Skinner
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D000068818:Cetuximab; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects / Q000528:radiation effects; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D006657:Histones / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D055503:Protein Multimerization / Q000187:drug effects; D011827:Radiation; D011836:Radiation Tolerance / Q000187:drug effects; D011878:Radiotherapy; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D047368:Tumor Burden / Q000187:drug effects / Q000528:radiation effects; D000071857:Tumor Suppressor p53-Binding Protein 1; D023041:Xenograft Model Antitumor Assays
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; C498301:TP53BP1 protein, human; D000071857:Tumor Suppressor p53-Binding Protein 1; D066246:ErbB Receptors; D017526:Receptor, IGF Type 1; D000068818:Cetuximab
keywords: Head and neck squamous cell carcinoma; IGF-1R and EGFR signaling; radiosensitivity; tumor response to radiation