Enhancement of Cetuximab-Induced Radiosensitization by JAK-1 Inhibition

BMC Cancer

Research Article

Hoa Q. Trummell¹  Christopher D. Willey¹  Andrew B. Bonner¹  Markus Bredel¹  James A. Bonner¹  Eddy S. Yang¹ 

[1] The University of Alabama at Birmingham, Department of Radiation Oncology, Hazelrig-Salter Radiation Oncology Center, Suite 2262, 1700 6th Avenue South, 35249, Birmingham, AL, UK;

关键词: Epidermal Growth Factor Receptor;    Cetuximab;    Human Head;    Epidermal Growth Factor Receptor Inhibition;    Epidermal Growth Factor Receptor Signaling;   

DOI  :  10.1186/s12885-015-1679-x

 received in 2014-12-31, accepted in 2015-10-02,  发布年份 2015

来源: Springer

【 摘 要 】

BackgroundIt 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.Methods/ResultsThe 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.ConclusionsThese 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.

【 授权许可】

CC BY   
© Bonner et al. 2015