Document Detail


Detection of impaired homologous recombination repair in NSCLC cells and tissues.
MedLine Citation:
PMID:  23399959     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
INTRODUCTION: Homologous recombination repair (HRR) is a critical pathway for the repair of DNA damage caused by cisplatin or poly-ADP ribose polymerase (PARP) inhibitors. HRR may be impaired by multiple mechanisms in cancer, which complicates assessing the functional HRR status in cells. Here, we monitored the ability of non-small-cell lung cancer (NSCLC) cells to form subnuclear foci of DNA repair proteins as a surrogate of HRR proficiency.
METHODS: We assessed clonogenic survival of 16 NSCLC cell lines in response to cisplatin, mitomycin C (MMC), and the PARP inhibitor olaparib. Thirteen tumor explants from patients with NSCLC were subjected to cisplatin ex vivo. Cells were assayed for foci of repair-associated proteins such as BRCA1, FANCD2, RAD51, and γ-H2AX.
RESULTS: Four cell lines (25%) showed an impaired RAD51 foci-forming ability in response to cisplatin. Impaired foci formation correlated with cellular sensitivity to cisplatin, MMC and olaparib. Foci responses complemented or superseded genomic information suggesting alterations in the ATM/ATR and FA/BRCA pathways. Because baseline foci in untreated cells did not predict drug sensitivity, we adapted an ex vivo biomarker assay to monitor damage-induced RAD51 foci in NSCLC explants from patients. Ex vivo cisplatin treatment of explants identified two tumors (15%) exhibiting compromised RAD51 foci induction.
CONCLUSIONS: A fraction of NSCLC harbors HRR defects that may sensitize the affected tumors to DNA-damaging agents including PARP inhibitors. We propose that foci-based functional biomarker assays represent a powerful tool for prospective determination of treatment sensitivity, but will require ex vivo techniques for induction of DNA damage to unmask the underlying HRR defect.
Authors:
Moritz Birkelbach; Natalie Ferraiolo; Liliana Gheorghiu; Heike N Pfäffle; Benedict Daly; Michael I Ebright; Cheryl Spencer; Carl O'Hara; Johnathan R Whetstine; Cyril H Benes; Lecia V Sequist; Lee Zou; Jochen Dahm-Daphi; Lisa A Kachnic; Henning Willers
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.    
Journal Detail:
Title:  Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer     Volume:  8     ISSN:  1556-1380     ISO Abbreviation:  J Thorac Oncol     Publication Date:  2013 Mar 
Date Detail:
Created Date:  2013-02-14     Completed Date:  2013-07-30     Revised Date:  2014-03-06    
Medline Journal Info:
Nlm Unique ID:  101274235     Medline TA:  J Thorac Oncol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  279-86     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Antibiotics, Antineoplastic / pharmacology
Antineoplastic Agents / pharmacology*
BRCA1 Protein / metabolism
Carcinoma, Non-Small-Cell Lung / diagnosis,  drug therapy,  genetics*
Cisplatin / pharmacology
DNA Damage / drug effects,  genetics
Fanconi Anemia Complementation Group D2 Protein / metabolism
Humans
Immunoenzyme Techniques
Lung Neoplasms / diagnosis,  drug therapy,  genetics*
Microscopy, Fluorescence
Mitomycin / pharmacology
Phthalazines / pharmacology
Piperazines / pharmacology
Poly(ADP-ribose) Polymerases / antagonists & inhibitors*
Rad51 Recombinase / metabolism
Recombination, Genetic / genetics*
Recombinational DNA Repair / drug effects,  genetics*
Tumor Cells, Cultured
Tumor Stem Cell Assay
Grant Support
ID/Acronym/Agency:
C06 CA059267/CA/NCI NIH HHS; C06 CA059267/CA/NCI NIH HHS; P50 CA090578/CA/NCI NIH HHS; P50 CA090578/CA/NCI NIH HHS; R01 GM097360/GM/NIGMS NIH HHS; R01 GM097360/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/AZD 2281; 0/Antibiotics, Antineoplastic; 0/Antineoplastic Agents; 0/BRCA1 Protein; 0/BRCA1 protein, human; 0/FANCD2 protein, human; 0/Fanconi Anemia Complementation Group D2 Protein; 0/Phthalazines; 0/Piperazines; 50SG953SK6/Mitomycin; EC 2.4.2.30/PARP1 protein, human; EC 2.4.2.30/Poly(ADP-ribose) Polymerases; EC 2.7.7.-/RAD51 protein, human; EC 2.7.7.-/Rad51 Recombinase; Q20Q21Q62J/Cisplatin
Comments/Corrections

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