AIMS: The central issue of resistance to radiation remains a significant 
challenge in the treatment of cancer despite improvements in treatment modality 
and emergence of new therapies. To facilitate the identification of molecular 
factors that elicit protection against ionizing radiation, we developed a 
matched model of radiation resistance for head and neck squamous cell cancer 
(HNSCC) and characterized its properties using quantitative mass spectrometry 
and complementary assays.
RESULTS: Functional network analysis of proteomics data identified DNA 
replication and base excision repair, extracellular matrix-receptor interaction, 
cell cycle, focal adhesion, and regulation of actin cytoskeleton as 
significantly up- or downregulated networks in resistant (rSCC-61) HNSCC cells. 
Upregulated proteins in rSCC-61 included a number of cytokeratins, fatty acid 
synthase, and antioxidant proteins. In addition, the rSCC-61 cells displayed two 
unexpected features compared with parental radiation-sensitive SCC-61 cells: (i) 
rSCC-61 had increased sensitivity to Erlotinib, a small-molecule inhibitor of 
epidermal growth factor receptor; and (ii) there was evidence of 
mesenchymal-to-epithelial transition in rSCC-61, confirmed by the expression of 
protein markers and functional assays (e.g., Vimentin, migration).
INNOVATION: The matched model of radiation resistance presented here shows that 
multiple signaling and metabolic pathways converge to produce the rSCC-61 
phenotype, and this points to the function of the antioxidant system as a major 
regulator of resistance to ionizing radiation in rSCC-61, a phenomenon further 
confirmed by analysis of HNSCC tumor samples.
CONCLUSION: The rSCC-61/SCC-61 model provides the opportunity for future 
investigations of the redox-regulated mechanisms of response to combined 
radiation and Erlotinib in a preclinical setting.