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 39-deoxy-39-18F-fluoro- thymidine (18F-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-xL 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-xL 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 18F-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 18F-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 18F-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 18F-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 18F-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. Conclusion: PET/CT with 18F-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-xL inhibitors.

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

SALVATORE, MARCO;DEL VECCHIO, SILVANA
2012

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 39-deoxy-39-18F-fluoro- thymidine (18F-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-xL 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-xL 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 18F-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 18F-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 18F-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 18F-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 18F-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. Conclusion: PET/CT with 18F-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-xL inhibitors.
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/426083
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 30
  • ???jsp.display-item.citation.isi??? 30
social impact