Automated quantitative analyses (AQUA) of cyclic-AMP-response-element-binding protein (CREB), phosphorylated CREB (pCREB), and ataxia-telangiectasia-mutated protein kinase (ATM) protein expression in patients (pts) undergoing thoracic radiation for locally advanced non-small cell lung cancer (NSCLC).
e13537 Background: Increased protein expression of CREB, a DNA damage-regulated transcription factor, has been associated with poor survival in advanced NSCLC. We have demonstrated that exposure of cancer cell lines to low dose ionizing radiation (IR) increased pCREB on a Ser133 residue. However, exposure to high dose IR correlated with pCREB on Ser121 by ATM, a master regulator of the cellular DNA damage response. This unusual bimodal response of CREB to IR, reflected by activation at low doses and attenuation at high doses, suggested that CREB may control cell fate decisions in response to DNA damage. We hypothesized that patterns of protein expression of CREB, pCREB Ser133, and ATM would predict treatment response in pts who have undergone radiotherapy for locally advanced NSCLC. Methods: Diagnostic tumor specimens were obtained from pts who underwent thoracic radiation in a clinical trial for locally advanced NSCLC. Protein expression of CREB, pCREB Ser133, and ATM was assessed by AQUA. Wilcoxon rank sum test was used to assess differences in protein expression. Univariate regression was conducted to evaluate protein expression and clinical outcomes. Kruskal Wallis test was used to assess protein expression and pneumonitis. Results: Sufficient tumor tissue was available for 35 of 79 pts enrolled. Best responses in 6 months included 12% CR, 73% PR, 9% SD, and 6% PD. Pre-treatment protein expression per AQUA analyses of CREB, pCREB Ser133, and ATM were not statistically associated with time to in-field progression, time to out-of-field progression, time to distant metastasis, best response, pneumonitis, or overall survival. Unexpectedly, increased expression of pCREB Ser133 was associated with durable anti-tumor response to radiation at a median duration of 14.6 months (p=0.03). Conclusions: Protein expression per AQUA of CREB, pCREB Ser133, and ATM did not confirm our hypotheses, possibly related to our limited sample size. Further analysis of the role of CREB in response to IR in cancer pts is ongoing.