TY - JOUR
T1 - Loss of DNA Damage Response in Neuroblastoma and Utility of a PARP Inhibitor
AU - Takagi, Masatoshi
AU - Yoshida, Misa
AU - Nemoto, Yoshino
AU - Tamaichi, Hiroyuki
AU - Tsuchida, Rika
AU - Seki, Masafumi
AU - Uryu, Kumiko
AU - Nishii, Rina
AU - Miyamoto, Satoshi
AU - Saito, Masahiro
AU - Hanada, Ryoji
AU - Kaneko, Hideo
AU - Miyano, Satoru
AU - Kataoka, Keisuke
AU - Yoshida, Kenichi
AU - Ohira, Miki
AU - Hayashi, Yasuhide
AU - Nakagawara, Akira
AU - Ogawa, Seishi
AU - Mizutani, Shuki
AU - Takita, Junko
N1 - Funding Information:
This work was supported by the Ministry of Education, Culture, Sports, Science, and Technology (MEXT) Grants-in-Aid for Scientific Research (23390271 to MT and SM; 26464568 to RT; 25253095 to JT); Japan Society for the Promotion of Science; Grants-in-Aid for Scientific Research and P-DIRECT; Ministry of Health, Labor and Welfare (MHLW); Health and Labor Sciences Research Grants; Research on Measures for Intractable Diseases; Research on Health Sciences Focusing on Drug Innovation; Japan Agency for Medical Research and Development (AMED); Japan Science and Technology Agency (JST); Core Research for Evolutional Science and Technology (CREST); Japan Health Sciences Foundation; P-CREATE; and the Princess Takamatsu Cancer Research Fund.
Publisher Copyright:
© The Author 2017. Published by Oxford University Press. All rights reserved.
PY - 2017/11/1
Y1 - 2017/11/1
N2 - Background: Neuroblastoma (NB) is the most common solid tumor found in children, and deletions within the 11q region are observed in 11% to 48% of these tumors. Notably, such tumors are associated with poor prognosis; however, little is known regarding the molecular targets located in 11q. Methods: Genomic alterations of ATM, DNA damage response (DDR)–associated genes located in 11q (MRE11A, H2AFX, and CHEK1), and BRCA1, BARD1, CHEK2, MDM2, and TP53 were investigated in 45 NB-derived cell lines and 237 fresh tumor samples. PARP (poly [ADP-ribose] polymerase) inhibitor sensitivity of NB was investigated in in vitro and in vivo xenograft models. All statistical tests were two-sided. Results: Among 237 fresh tumor samples, ATM, MRE11A, H2AFX, and/or CHEK1 loss or imbalance in 11q was detected in 20.7% of NBs, 89.8% of which were stage III or IV. An additional 7.2% contained ATM rare single nucleotide variants (SNVs). Rare SNVs in DDR-associated genes other than ATM were detected in 26.4% and were mutually exclusive. Overall, samples with SNVs and/or copy number alterations in these genes accounted for 48.4%. ATM-defective cells are known to exhibit dysfunctions in homologous recombination repair, suggesting a potential for synthetic lethality by PARP inhibition. Indeed, 83.3% NB-derived cell lines exhibited sensitivity to PARP inhibition. In addition, NB growth was markedly attenuated in the xenograft group receiving PARP inhibitors (sham-treated vs olaprib-treated group; mean [SD] tumor volume of sham-treated vs olaprib-treated groups = 7377 [1451] m3 vs 298 [312] m3, P = .001, n = 4). Conclusions: Genomic alterations of DDR-associated genes including ATM, which regulates homologous recombination repair, were observed in almost half of NBs, suggesting that synthetic lethality could be induced by treatment with a PARP inhibitor. Indeed, DDR-defective NB cell lines were sensitive to PARP inhibitors. Thus, PARP inhibitors represent candidate NB therapeutics.
AB - Background: Neuroblastoma (NB) is the most common solid tumor found in children, and deletions within the 11q region are observed in 11% to 48% of these tumors. Notably, such tumors are associated with poor prognosis; however, little is known regarding the molecular targets located in 11q. Methods: Genomic alterations of ATM, DNA damage response (DDR)–associated genes located in 11q (MRE11A, H2AFX, and CHEK1), and BRCA1, BARD1, CHEK2, MDM2, and TP53 were investigated in 45 NB-derived cell lines and 237 fresh tumor samples. PARP (poly [ADP-ribose] polymerase) inhibitor sensitivity of NB was investigated in in vitro and in vivo xenograft models. All statistical tests were two-sided. Results: Among 237 fresh tumor samples, ATM, MRE11A, H2AFX, and/or CHEK1 loss or imbalance in 11q was detected in 20.7% of NBs, 89.8% of which were stage III or IV. An additional 7.2% contained ATM rare single nucleotide variants (SNVs). Rare SNVs in DDR-associated genes other than ATM were detected in 26.4% and were mutually exclusive. Overall, samples with SNVs and/or copy number alterations in these genes accounted for 48.4%. ATM-defective cells are known to exhibit dysfunctions in homologous recombination repair, suggesting a potential for synthetic lethality by PARP inhibition. Indeed, 83.3% NB-derived cell lines exhibited sensitivity to PARP inhibition. In addition, NB growth was markedly attenuated in the xenograft group receiving PARP inhibitors (sham-treated vs olaprib-treated group; mean [SD] tumor volume of sham-treated vs olaprib-treated groups = 7377 [1451] m3 vs 298 [312] m3, P = .001, n = 4). Conclusions: Genomic alterations of DDR-associated genes including ATM, which regulates homologous recombination repair, were observed in almost half of NBs, suggesting that synthetic lethality could be induced by treatment with a PARP inhibitor. Indeed, DDR-defective NB cell lines were sensitive to PARP inhibitors. Thus, PARP inhibitors represent candidate NB therapeutics.
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U2 - 10.1093/jnci/djx062
DO - 10.1093/jnci/djx062
M3 - Article
C2 - 29059438
AN - SCOPUS:85033609243
SN - 0027-8874
VL - 109
JO - Journal of the National Cancer Institute
JF - Journal of the National Cancer Institute
IS - 11
M1 - djx062
ER -
