title: The effect of a dimeric Affibody molecule (ZEGFR:1907)2 targeting EGFR             in combination with radiation in colon cancer cell lines.
abstract: The epidermal growth factor receptor (EGFR) is frequently overexpressed             in colorectal cancer and is therefore an attractive target for treatment. (ZEGFR:1907)2             is a newly developed dimeric affibody molecule with high affinity to the extracellular             part of EGFR. In this study, we evaluated the cytotoxic effects of (ZEGFR:1907)2             in combination with external radiation and the possible inhibitory effects in             the EGFR signalling pathways in the colon cancer cell lines HT-29 and HCT116.             The effects were compared with an EGFR antibody (cetuximab) and the tyrosine kinase             inhibitors (erlotinib and sunitinib). These cell lines are genotypically different             with respect to e.g. KRAS and BRAF mutational status, recently shown to be of             clinical significance for therapeutic effects. Both cell lines express approximately             100,000-150,000 EGFRs per cell but differ in the radiation response (HCT116, SF2=0.28             and HT-29, SF2=0.70). Exposure to (ZEGFR:1907)2 produced a small, but significant,             reduction in survival in HCT116 but did not affect HT-29 cells. Similar results             were obtained after exposure to EGF and the EGFR antibody cetuximab. The EGFR             tyrosine kinase targeting inhibitor erlotinib and the multi-tyrosine kinase inhibitor             sunitinib reduced survival in both cell lines. However, none of the drugs had             any significant radiosensitizing effects in combination with radiation. Akt and             Erk are central proteins in the EGFR downstream signalling and in the cellular             response to ionizing radiation. The activation of Akt (Ser 473) and Erk (Thr202/Tyr204)             by radiation was both dose- and time-dependent. However the activation of EGFR             was not clearly affected by radiation. Neither (ZEGFR:1907)2 nor any of the other             drugs were able to completely inactivate Akt or Erk. On the contrary, erlotinib             stimulated Akt phosphorylation in both cell lines and in HCT116 cells Erk was             activated. Overall the results illustrate the complexity in response to radiation             and drugs in cells with differential phenotypic status.
authors: Section of Biomedical Radiation Sciences, Department of Radiology, Oncology and Radiation Science, Rudbeck Laboratory, Uppsala University, S-751 85 Uppsala, Sweden. sara.sahlberg@bms.uu.se
authors: Sara
authors: S
authors: Häggblad Sahlberg
authors: Diana
authors: D
authors: Spiegelberg
authors: Johan
authors: J
authors: Lennartsson
authors: Peter
authors: P
authors: Nygren
authors: Bengt
authors: B
authors: Glimelius
authors: Bo
authors: B
authors: Stenerlöw
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D000068818:Cetuximab; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000532:radiotherapy*; D016503:Drug Delivery Systems; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D000069347:Erlotinib Hydrochloride; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D011799:Quinazolines / Q000494:pharmacology; D011838:Radiation-Sensitizing Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D011993:Recombinant Fusion Proteins / Q000493:pharmacokinetics / Q000494:pharmacology*; D015398:Signal Transduction
chemical_list: C569382:(Z(EGFR)-1907)2 affibody; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D011799:Quinazolines; D011838:Radiation-Sensitizing Agents; D011993:Recombinant Fusion Proteins; D004815:Epidermal Growth Factor; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D000068818:Cetuximab