Detection of impaired homologous recombination repair in NSCLC cells and tissues
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Detection of impaired homologous recombination repair in NSCLC cells and tissues. / Birkelbach, Moritz; Ferraiolo, Natalie; Gheorghiu, Liliana; Pfäffle, Heike N; Daly, Benedict; Ebright, Michael I; Spencer, Cheryl; O'Hara, Carl; Whetstine, Johnathan R; Benes, Cyril H; Sequist, Lecia V; Zou, Lee; Dahm-Daphi, Jochen; Kachnic, Lisa A; Willers, Henning.
in: J THORAC ONCOL, Jahrgang 8, Nr. 3, 01.03.2013, S. 279-86.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - Detection of impaired homologous recombination repair in NSCLC cells and tissues
AU - Birkelbach, Moritz
AU - Ferraiolo, Natalie
AU - Gheorghiu, Liliana
AU - Pfäffle, Heike N
AU - Daly, Benedict
AU - Ebright, Michael I
AU - Spencer, Cheryl
AU - O'Hara, Carl
AU - Whetstine, Johnathan R
AU - Benes, Cyril H
AU - Sequist, Lecia V
AU - Zou, Lee
AU - Dahm-Daphi, Jochen
AU - Kachnic, Lisa A
AU - Willers, Henning
PY - 2013/3/1
Y1 - 2013/3/1
N2 - 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 Foci responses complemented or superseded genomic information suggesting alterations in the ATM/ATR and FA/BRCA pathways.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.
AB - 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.
KW - Antibiotics, Antineoplastic
KW - Antineoplastic Agents
KW - BRCA1 Protein
KW - Carcinoma, Non-Small-Cell Lung
KW - Cisplatin
KW - DNA Damage
KW - Fanconi Anemia Complementation Group D2 Protein
KW - Humans
KW - Immunoenzyme Techniques
KW - Lung Neoplasms
KW - Microscopy, Fluorescence
KW - Mitomycin
KW - Phthalazines
KW - Piperazines
KW - Poly(ADP-ribose) Polymerases
KW - Rad51 Recombinase
KW - Recombination, Genetic
KW - Recombinational DNA Repair
KW - Tumor Cells, Cultured
KW - Tumor Stem Cell Assay
U2 - 10.1097/JTO.0b013e31827ecf83
DO - 10.1097/JTO.0b013e31827ecf83
M3 - SCORING: Journal article
C2 - 23399959
VL - 8
SP - 279
EP - 286
JO - J THORAC ONCOL
JF - J THORAC ONCOL
SN - 1556-0864
IS - 3
ER -