title: Enhancement of Cetuximab-Induced Radiosensitization by JAK-1 Inhibition.
abstract: BACKGROUND
  It is known that cetuximab (an epidermal growth factor receptor [EGFr] inhibitor) is a radiosensitizer. Also, cetuximab is known to only partially inhibit the signal transducer and activator of transcription - 3 (STAT-3); a mediator of protection from apoptosis. Studies were performed to determine if the radiosensitizing effects of cetuximab could be enhanced with the addition of an inhibitor of STAT-3.
  
  
  RESULTS
  The interaction of JAK-STAT-3 inhibition ([JAK1i]; Calbiochem, LaJolla, CA) and EGFr inhibition (cetuximab) was assessed with and without radiation. Four human head and neck cell lines were studied: UM-SCC-1 and UM-SCC-5, and two modified UM-SCC-5 lines; a STAT-3 knockdown line (STAT-3-2.4) and control (NEG-4.17). Exposure to either 0.5 μg/ml of cetuximab or 1 μM JAK1i for 8 or 24 h resulted in reduced activated STAT-3 (immunoblot), and the combination treatment showed greater reduction in activated STAT-3 compared to the individual treatments. The use of either post-radiation JAK1i (1 μM for 72 h) or post-radiation cetuximab (0.5 μg/ml) enhanced radiation-induced anti-proliferative and apoptotic effects but the greatest enhancement was seen when cells were exposed to both JAK1i and cetuximab post-radiation. Similar results were seen for radiosensitization as assessed by colony formation. Finally, the combination treatment of JAK1i (1 μM) and cetuximab (0.5 μg/ml), following radiation, resulted in an increase of unrepaired radiation-induced DNA double strand breaks at 6 and 24 h after radiation compared to the use of post-radiation JAK1i or cetuximab alone as delineated by neutral comet assay.
  
  
  CONCLUSIONS
  These findings suggest that dual inhibition of EGFr (cetuximab) and JAK-STAT-3 (JAK1i) leads to greater radiosensitization than with either cetuximab or JAK1i alone and suggests that this combination treatment may be clinically relevant even for tumors with a marked range of STAT-3 activity.
authors.affiliation: The University of Alabama at Birmingham, Department of Radiation Oncology, Hazelrig-Salter Radiation Oncology Center, Suite 2262, 1700 6th Avenue South, Birmingham, AL, 35249, UK. gesims@uabmc.edu.
authors.forename: James A
authors.initials: JA
authors.lastname: Bonner
authors.affiliation: The University of Alabama at Birmingham, Department of Radiation Oncology, Hazelrig-Salter Radiation Oncology Center, Suite 2262, 1700 6th Avenue South, Birmingham, AL, 35249, UK. trummell@uab.edu.
authors.forename: Hoa Q
authors.initials: HQ
authors.lastname: Trummell
authors.affiliation: The University of Alabama at Birmingham, Department of Radiation Oncology, Hazelrig-Salter Radiation Oncology Center, Suite 2262, 1700 6th Avenue South, Birmingham, AL, 35249, UK. pjbonner@bellsouth.net.
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Bonner
authors.affiliation: The University of Alabama at Birmingham, Department of Radiation Oncology, Hazelrig-Salter Radiation Oncology Center, Suite 2262, 1700 6th Avenue South, Birmingham, AL, 35249, UK. cwilley@uabmc.edu.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Willey
authors.affiliation: The University of Alabama at Birmingham, Department of Radiation Oncology, Hazelrig-Salter Radiation Oncology Center, Suite 2262, 1700 6th Avenue South, Birmingham, AL, 35249, UK. mbredel@uabmc.edu.
authors.forename: Markus
authors.initials: M
authors.lastname: Bredel
authors.affiliation: The University of Alabama at Birmingham, Department of Radiation Oncology, Hazelrig-Salter Radiation Oncology Center, Suite 2262, 1700 6th Avenue South, Birmingham, AL, 35249, UK. eyang@uabmc.edu.
authors.forename: Eddy S
authors.initials: ES
authors.lastname: Yang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000068818:Cetuximab / Q000494:pharmacology*; D004249:DNA Damage / Q000528:radiation effects; D004260:DNA Repair / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006801:Humans; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011838:Radiation-Sensitizing Agents; D053613:Janus Kinase 1; D000068818:Cetuximab