ABSTRACT
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.
Subject(s)
Carcinoma, Squamous Cell/drug therapy , Carcinoma, Squamous Cell/radiotherapy , Head and Neck Neoplasms/drug therapy , Head and Neck Neoplasms/radiotherapy , Quinazolines/pharmacology , Radiation Tolerance/radiation effects , Carcinoma, Squamous Cell/genetics , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/metabolism , Erlotinib Hydrochloride , Head and Neck Neoplasms/genetics , Humans , Phenotype , Phosphorylation/drug effects , Radiation, Ionizing , Squamous Cell Carcinoma of Head and Neck , Tumor Cells, CulturedABSTRACT
BACKGROUND: Concurrent radiation and chemotherapy is the standard of care for good performance status patients with stage III non-small cell lung cancer. Locoregional control remains a significant factor relating to poor outcome. Preclinical and early clinical data suggest that docetaxel and gefitinib have radiosensitizing activity. This study sought to define the maximum tolerated dose of weekly docetaxel that could be given with daily gefitinib and concurrent thoracic radiation therapy. PATIENTS AND MATERIALS: Patients with histologically confirmed, inoperable stage III non-small cell lung cancer and good performance status (Eastern Cooperative Oncology Group 0-1) were eligible for this study. Patients received three-dimensional conformal thoracic radiation to a dose of 70 Gy concurrently with oral gefitinib at a dose of 250 mg daily and intravenous, weekly docetaxel at escalating doses from 15 to 30 mg/m2 in cohorts of patients. Patients were given a 2-week rest period after the concurrent therapy, during which they received only gefitinib. After the 2-week rest period, patients received consolidation chemotherapy with docetaxel 75 mg/m2 given every 21 days for two cycles. Maintenance gefitinib was continued until disease progression or study completion. RESULTS: Sixteen patients were enrolled on the study between December 2003 and April 2007 with the following characteristics: median age, 64 years (range 43-79 years); M/F: 9/7; and performance status 0/1, 1/15. Dose-limiting pulmonary toxicity and esophagitis were encountered at a weekly docetaxel dose of 25 mg/m2, resulting in a maximum tolerated dose of 20 mg/m2/wk. Overall, grade 3/4 hematologic toxicity was observed in 27% of patients. Grade 3/4 esophageal and pulmonary toxicities were reported in 27% and 20% of patients, respectively. The overall response rate was 46%, and the median survival for all patients was 21 months. CONCLUSIONS: Concurrent thoracic radiation with weekly docetaxel and daily gefitinib is feasible but results in moderate toxicity. For further studies, the recommended weekly docetaxel dose for this chemoradiation regimen is 20 mg/m2.
