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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, Vol. 8, No. 3, 01.03.2013, p. 279-86.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Birkelbach, M, Ferraiolo, N, Gheorghiu, L, Pfäffle, HN, Daly, B, Ebright, MI, Spencer, C, O'Hara, C, Whetstine, JR, Benes, CH, Sequist, LV, Zou, L, Dahm-Daphi, J, Kachnic, LA & Willers, H 2013, 'Detection of impaired homologous recombination repair in NSCLC cells and tissues', J THORAC ONCOL, vol. 8, no. 3, pp. 279-86. https://doi.org/10.1097/JTO.0b013e31827ecf83

APA

Birkelbach, M., Ferraiolo, N., Gheorghiu, L., Pfäffle, H. N., Daly, B., Ebright, M. I., Spencer, C., O'Hara, C., Whetstine, J. R., Benes, C. H., Sequist, L. V., Zou, L., Dahm-Daphi, J., Kachnic, L. A., & Willers, H. (2013). Detection of impaired homologous recombination repair in NSCLC cells and tissues. J THORAC ONCOL, 8(3), 279-86. https://doi.org/10.1097/JTO.0b013e31827ecf83

Vancouver

Birkelbach M, Ferraiolo N, Gheorghiu L, Pfäffle HN, Daly B, Ebright MI et al. Detection of impaired homologous recombination repair in NSCLC cells and tissues. J THORAC ONCOL. 2013 Mar 1;8(3):279-86. https://doi.org/10.1097/JTO.0b013e31827ecf83

Bibtex

@article{7c2340e314e440888baa5f663a616e0d,
title = "Detection of impaired homologous recombination repair in NSCLC cells and tissues",
abstract = "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.",
keywords = "Antibiotics, Antineoplastic, Antineoplastic Agents, BRCA1 Protein, Carcinoma, Non-Small-Cell Lung, Cisplatin, DNA Damage, Fanconi Anemia Complementation Group D2 Protein, Humans, Immunoenzyme Techniques, Lung Neoplasms, Microscopy, Fluorescence, Mitomycin, Phthalazines, Piperazines, Poly(ADP-ribose) Polymerases, Rad51 Recombinase, Recombination, Genetic, Recombinational DNA Repair, Tumor Cells, Cultured, Tumor Stem Cell Assay",
author = "Moritz Birkelbach and Natalie Ferraiolo and Liliana Gheorghiu and Pf{\"a}ffle, {Heike N} and Benedict Daly and Ebright, {Michael I} and Cheryl Spencer and Carl O'Hara and Whetstine, {Johnathan R} and Benes, {Cyril H} and Sequist, {Lecia V} and Lee Zou and Jochen Dahm-Daphi and Kachnic, {Lisa A} and Henning Willers",
year = "2013",
month = mar,
day = "1",
doi = "10.1097/JTO.0b013e31827ecf83",
language = "English",
volume = "8",
pages = "279--86",
journal = "J THORAC ONCOL",
issn = "1556-0864",
publisher = "International Association for the Study of Lung Cancer",
number = "3",

}

RIS

TY - JOUR

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 -