Document Detail


Short-course treatment with gefitinib enhances curative potential of radiation therapy in a mouse model of human non-small cell lung cancer.
MedLine Citation:
PMID:  24606853     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
PURPOSE: To evaluate the combination of radiation and an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) in preclinical models of human non-small cell lung cancer.
METHODS AND MATERIALS: Sensitivity to an EGFR TKI (gefitinib) or radiation was assessed using proliferation assays and clonogenic survival assays. Effects on receptor signal transduction pathways (pEGFR, pAKT, pMAPK) and apoptosis (percentage of cleaved PARP Poly (ADP-ribose) polymerase (PARP)) were assessed by Western blotting. Radiation-induced DNA damage was assessed by γH2AX immunofluorescence. Established (≥ 100 mm(3)) EGFR-mutated (HCC287) or EGFR wild-type (A549) subcutaneous xenografts were treated with radiation (10 Gy, day 1) or gefitinib (50 mg/kg, orally, on days 1-3) or both.
RESULTS: In non-small cell lung cancer (NSCLC) cell lines with activating EGFR mutations (PC9 or HCC827), gefitinib treatment markedly reduced pEGFR, pAKT, and pMAPK levels and was associated with an increase in cleaved PARP but not in γH2AX foci. Radiation treatment increased the mean number of γH2AX foci per cell but did not significantly affect EGFR signaling. In contrast, NSCLC cell lines with EGFR T790M (H1975) or wild-type EGFR (A549) were insensitive to gefitinib treatment. The combination of gefitinib and radiation treatment in cell culture produced additive cell killing with no evidence of synergy. In xenograft models, a short course of gefitinib (3 days) did not significantly increase the activity of radiation treatment in wild-type EGFR (A549) tumors (P=.27), whereas this combination markedly increased the activity of radiation (P<.001) or gefitinib alone (P=.002) in EGFR-mutated HCC827 tumors, producing sustained tumor regressions.
CONCLUSIONS: Gefitinib treatment increases clonogenic cell killing by radiation but only in cell lines sensitive to gefitinib alone. Our data suggest additive rather than synergistic interactions between gefitinib and radiation and that a combination of short-course gefitinib and high-dose/-fraction radiation may have the greatest potential against the subsets of lung cancers harboring activating mutations in the EGFR gene.
Authors:
Sivan M Bokobza; Yanyan Jiang; Anika M Weber; Aoife M Devery; Anderson J Ryan
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  International journal of radiation oncology, biology, physics     Volume:  88     ISSN:  1879-355X     ISO Abbreviation:  Int. J. Radiat. Oncol. Biol. Phys.     Publication Date:  2014 Mar 
Date Detail:
Created Date:  2014-03-10     Completed Date:  2014-04-24     Revised Date:  2014-10-28    
Medline Journal Info:
Nlm Unique ID:  7603616     Medline TA:  Int J Radiat Oncol Biol Phys     Country:  United States    
Other Details:
Languages:  eng     Pagination:  947-54     Citation Subset:  IM    
Copyright Information:
Copyright © 2014 Elsevier Inc. All rights reserved.
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MeSH Terms
Descriptor/Qualifier:
Animals
Antineoplastic Agents / therapeutic use*
Carcinoma, Non-Small-Cell Lung / drug therapy*,  radiotherapy*
Cell Line, Tumor
Combined Modality Therapy / methods
Disease Models, Animal
Genes, erbB-1
Heterografts
Histones / metabolism
Humans
Lung Neoplasms / drug therapy*,  genetics,  radiotherapy*
Mice
Mitogen-Activated Protein Kinase Kinases / metabolism
Poly(ADP-ribose) Polymerases / metabolism
Proto-Oncogene Proteins c-akt / metabolism
Quinazolines / therapeutic use*
Receptor, Epidermal Growth Factor / genetics,  metabolism
Xenograft Model Antitumor Assays
Grant Support
ID/Acronym/Agency:
MC_PC_12006//Medical Research Council
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/H2AFX protein, human; 0/Histones; 0/Quinazolines; EC 2.4.2.30/Poly(ADP-ribose) Polymerases; EC 2.7.10.1/Receptor, Epidermal Growth Factor; EC 2.7.11.1/Proto-Oncogene Proteins c-akt; EC 2.7.12.2/Mitogen-Activated Protein Kinase Kinases; S65743JHBS/gefitinib

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