Reference - Detail
|Author||Takagi M, Yoshida M, Nemoto Y, Tamaichi H, Tsuchida R, Seki M, Uryu K, Nishii R, Miyamoto S, Saito M, Hanada R, Kaneko H, Miyano S, Kataoka K, Yoshida K, Ohira M, Hayashi Y, Nakagawara A, Ogawa S, Mizutani S, Takita J.|
|Title||Loss of DNA Damage Response in Neuroblastoma and Utility of a PARP Inhibitor.|
|Journal||J Natl Cancer Inst|
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 invivo 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  m 3 vs 298  m 3 , 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.
|MeSH||Animals Ataxia Telangiectasia Mutated Proteins / genetics Cell Line, Tumor Checkpoint Kinase 1 / genetics Checkpoint Kinase 2 / genetics Child Chromosomes, Human, Pair 11* DNA Damage DNA Repair* DNA-Binding Proteins / genetics Gene Deletion* Heterografts Histones / genetics Humans MRE11 Homologue Protein Mice Neuroblastoma / drug therapy* Neuroblastoma / genetics* Neuroblastoma / mortality Neuroblastoma / pathology Phthalazines / therapeutic use* Piperazines / therapeutic use* Poly(ADP-ribose) Polymerase Inhibitors / therapeutic use* Proto-Oncogene Proteins c-mdm2 / genetics Tumor Suppressor Protein p53 / genetics Tumor Suppressor Proteins / genetics Ubiquitin-Protein Ligases / genetics|
|Human and Animal Cells||CHP-134(RCB0487) NB9(RCB0477) NB69(RCB0480)|