title: 3'-deoxy-3'-18F-fluorothymidine PET/CT to guide therapy with epidermal growth factor receptor antagonists and Bcl-xL inhibitors in non-small cell lung cancer.
abstract: Epidermal growth factor receptor (EGFR) mutational status, activation of downstream signaling, and effective apoptotic cascade are all factors that may affect the tumor response to EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC). Here we test whether 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) PET/CT can provide clues for the selection of patients with NSCLC as candidates for treatment with reversible and irreversible EGFR TKIs or combination treatment with Bcl-x(L) inhibitors.
  
  
  METHODS
  HCC827, H1975, and H1650 NSCLC cells were subcutaneously injected into flanks of nude mice. Tumor-bearing animals were treated daily for 3 d by oral gavage with erlotinib at 50 and 150 mg/kg, CL-387,785 (an irreversible EGFR TKI) at 50 mg/kg, WZ4002 (a more potent irreversible EGFR TKI) at 25 and 50 mg/kg, ABT-263 (a Bcl-x(L) inhibitor) at 6.25 mg/kg, and a combination of erlotinib (50 mg/kg) and ABT-263 (6.25 mg/kg). Imaging studies were performed before and after 3 d of treatment by intravenous injection of 7.4 MBq of (18)F-FLT and small-animal PET/CT of animals at 1 h after injection. Quantitative analysis of reconstructed images of baseline and posttreatment scans was performed, and the percentage change in (18)F-FLT uptake in each animal was determined. Tumor sections were tested for Ki67 immunostaining and the percentage of apoptotic cells.
  
  
  RESULTS
  Sensitive tumors (HCC827) showed mean decreases in (18)F-FLT uptake of 45% and 28% with high- and low-dose regimens of erlotinib, respectively. Resistant NSCLC cells bearing a T790M mutation (H1975) showed mean increases in (18)F-FLT uptake of 27% and 33% with high and low doses of erlotinib, respectively. Treatment with CL-387,785, low-dose WZ4002, and high-dose WZ4002 caused mean decreases in tracer uptake of 21%, 26%, and 36%, respectively. NSCLC cells that were resistant because of dysregulation of Bcl-2 family members (H1650) showed mean reductions in (18)F-FLT uptake of 49% and 23% with high and low doses of erlotinib, respectively, whereas the addition of ABT-263 did not affect tracer uptake but significantly increased the percentage of apoptotic cells in tumor sections.
  
  
  CONCLUSIONS
  PET/CT with (18)F-FLT may contribute to the selection of patients who may benefit from treatment with reversible and irreversible EGFR TKIs and may provide clues about which patients with NSCLC may be candidates for combination treatment with erlotinib and Bcl-x(L) inhibitors.
authors.affiliation: Institute of Biostructures and Bioimages, National Research Council, Naples, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Zannetti
authors.forename: Francesca
authors.initials: F
authors.lastname: Iommelli
authors.forename: Antonio
authors.initials: A
authors.lastname: Speranza
authors.forename: Marco
authors.initials: M
authors.lastname: Salvatore
authors.forename: Silvana
authors.initials: S
authors.lastname: Del Vecchio
mesh_terms: D000814:Aniline Compounds / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000000981:diagnostic imaging* / Q000188:drug therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015224:Dideoxynucleosides; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D000069347:Erlotinib Hydrochloride; D005260:Female; D007091:Image Processing, Computer-Assisted; D008175:Lung Neoplasms / Q000000981:diagnostic imaging* / Q000188:drug therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D064847:Multimodal Imaging / Q000379:methods*; D049268:Positron-Emission Tomography; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011799:Quinazolines / Q000627:therapeutic use; D019275:Radiopharmaceuticals; D013449:Sulfonamides / Q000627:therapeutic use; D014057:Tomography, X-Ray Computed; D051020:bcl-X Protein / Q000037:antagonists & inhibitors*
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; D015224:Dideoxynucleosides; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D019275:Radiopharmaceuticals; D013449:Sulfonamides; D051020:bcl-X Protein; C118029:CL 387785; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; C002854:alovudine; C528561:navitoclax