Early Detection of Erlotinib Treatment Response in NSCLC by 3′-Deoxy-3′-[\(^{18}F\)]-Fluoro-L-Thymidine ([\(^{18}F\)]FLT) Positron Emission Tomography (PET)

Abstract

Background: 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. Methodology/Principal Findings: We performed a systematic comparison of 3′-Deoxy-3′-[(^{18}F)]-fluoro-L-thymidine ([(^{18}F)]FLT) and 2-[(^{18}F)]-fluoro-2-deoxy-D-glucose ([(^{18}F)]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 [(^{18}F)]FLT uptake after only two days of treatment, [(^{18}F)]FDG PET based imaging revealed no consistent reduction in tumor glucose uptake. In sensitive tumors, a decrease in [(^{18}F)]FLT PET but not [(^{18}F)]FDG PET uptake correlated with cell cycle arrest and induction of apoptosis. The reduction in [(^{18}F)]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 [(^{18}F)]FLT PET response of tumors expressing the T790M erlotinib resistance mutation of EGFR. Conclusions: [(^{18}F)]FLT PET enables robust identification of erlotinib response in EGFR-dependent tumors at a very early stage. [(^{18}F)]FLT PET imaging may represent an appropriate method for early prediction of response to EGFR TKI treatment in patients with NSCLC.