Abstract
The combination of radiotherapy and pharmacological inhibition of cellular signal transduction pathways offers promising strategies for enhanced cancer cell inactivation. However, the molecular effects of kinase inhibitors especially on DNA damage detection and repair after X-irradiation have to be understood to facilitate the development of efficient and personalized treatment regimens. Therefore, we applied differential proteomics for analyzing inhibitor-induced changes in either chromatin-bound or phosphorylated nuclear proteins. The effect of the multi kinase inhibitor sorafenib on DNA repair, chromatin binding and phosphorylation of nuclear proteins was analyzed in UT-SCC 42B head and neck cancer cells using metabolic labeling based differential proteomics (SILAC). Sorafenib significantly inhibited DNA repair but failed to significantly affect chromatin interactions of 90 quantified proteins. In contrast, analyzing nuclear phospho-proteins following sorafenib treatment, we detected quantitative changes in 9 out of 59 proteins, including DNA-repair proteins. In conclusion, the analysis of nuclear phospho-proteins by differential proteomics is an effective tool for determining the molecular effects of kinase inhibitors on X-irradiated cells. Analyzing chromatin binding might be less promising.
Highlights
To improve cancer treatment radiotherapy is combined with radiation response modifiers
The effect of the multi kinase inhibitor sorafenib on DNA repair, chromatin binding and phosphorylation of nuclear proteins was analyzed in UT-SCC 42B head and neck cancer cells using metabolic labeling based differential proteomics (SILAC)
The most prominent example is the combination of radiotherapy with cetuximab, an inhibitory antibody directed against the epidermal growth factor receptor (EGFR) which is used to treat patients with head and neck squamous cell carcinoma
Summary
To improve cancer treatment radiotherapy is combined with radiation response modifiers (radiosensitizers). In this context numerous kinase inhibitors blocking important cellular signal transduction pathways such as EGFR-, mTOR or Raf-signaling have been tested over the past years in combination with X-irradiation (IR) [1]. The most prominent example is the combination of radiotherapy with cetuximab, an inhibitory antibody directed against the epidermal growth factor receptor (EGFR) which is used to treat patients with head and neck squamous cell carcinoma Many other antibodies and small molecule inhibitors have been tested in combination with IR in pre-clinical as well as clinical studies with partly promising results [1]. For effective prediction the molecular effects of the inhibitors on the irradiated cells have to be understood
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
