57 QUANTITATIVE ASSESSMENT OF TUMOR GLUCOSE UTILIZATION FOR PREDICTION OF RESPONSE TO TREATMENT WITH THE EPIDERMAL GROWTH FACTOR RECEPTOR KINASE INHIBITOR GEFITINIB (IRESSA)

ObjectivesSmall molecule inhibitors of the epidermal growth factor receptor (EGFR) kinase have recently been introduced for treatment of non-small cell lung cancer (NSCLC). However, these new drugs are only effective in approximately 10% of patients and there are no diagnostic tests to predict tumor response. The aim of this study was to evaluate whether changes in tumor glucose utilization, as assessed by positron emission tomography with the glucose analog fluorodeoxyglucose (FDG-PET), may be used to predict response to EGFR-kinase inhibitors early in the course of therapy.MethodsGlucose metabolism was studied in three human cancer cell lines with varying sensitivity to the EGFR-kinase inhibitor gefitinib. FDG uptake (a measure of glucose transport and phosphorylation) was determined in cell cultures and by microPET imaging of xenografts subcutaneously injected into SCID mice. To elucidate the mechanisms for treatment-induced changes in FDG uptake, glucose transport was assessed with the metabolically stable glucose analogue 3OMDG, and hexokinase activity of cell extracts was measured photometrically.ResultsIn the highly sensitive HCC4006 cells, FDG uptake decreased within 2 hours of treatment with 0.2 μM gefitinib and was only 30% of controls after 2 days. Reduced FDG uptake was due to decreased transport (influx constant of 3OMDG for treated and untreated cells 3.9/min and 21/min, respectively) and not due to impaired phosphorylation (hexokinase activity 277 and 253 mU/mg, respectively). Gefitinib-resistant A549 cells showed no change in FDG uptake and the moderately sensitive A431 cells demonstrated an intermediate response. In vivo, FDG uptake of A431 xenografts significantly decreased after two doses of gefitinib. Relative to controls FDG uptake of tumors treated with 75 mg/kg and 100 mg/kg was 64% ± 1% and 49% ± 5%, respectively.ConclusionIn sensitive tumors gefitinib causes a rapid decrease in glucose transport, which can be measured by PET imaging. These findings encourage the use of FDG-PET to predict response to EGFR kinase inhibitors in NSCLC.