Roland T. Ullrich 1 , 2 , Thomas Zander 6 , Bernd Neumaier 1 , Mirjam Koker 1 , Takeshi Shimamura 4 , 5 , Yannic Waerzeggers 1 , Christa L. Borgman 4 , 5 , Samir Tawadros 6 , Hongfeng Li 1 , Martin L. Sos 1 , Heiko Backes 1 , Geoffrey I. Shapiro 4 , 5 , Jürgen Wolf 6 , Andreas H. Jacobs 1 , 2 , 3 , Roman K. Thomas 1 , 6 , 7 , * , Alexandra Winkeler 1 , 2
12 December 2008
Inhibition of the epidermal growth factor receptor (EGFR) has shown clinical success in patients with advanced non-small cell lung cancer (NSCLC). Somatic mutations of EGFR were found in lung adenocarcinoma that lead to exquisite dependency on EGFR signaling; thus patients with EGFR-mutant tumors are at high chance of response to EGFR inhibitors. However, imaging approaches affording early identification of tumor response in EGFR-dependent carcinomas have so far been lacking.
We performed a systematic comparison of 3′-Deoxy-3′-[ 18F]-fluoro-L-thymidine ([ 18F]FLT) and 2-[ 18F]-fluoro-2-deoxy-D-glucose ([ 18F]FDG) positron emission tomography (PET) for their potential to identify response to EGFR inhibitors in a model of EGFR-dependent lung cancer early after treatment initiation. While erlotinib-sensitive tumors exhibited a striking and reproducible decrease in [ 18F]FLT uptake after only two days of treatment, [ 18F]FDG PET based imaging revealed no consistent reduction in tumor glucose uptake. In sensitive tumors, a decrease in [ 18F]FLT PET but not [ 18F]FDG PET uptake correlated with cell cycle arrest and induction of apoptosis. The reduction in [ 18F]FLT PET signal at day 2 translated into dramatic tumor shrinkage four days later. Furthermore, the specificity of our results is confirmed by the complete lack of [ 18F]FLT PET response of tumors expressing the T790M erlotinib resistance mutation of EGFR.