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Ref Type Journal Article
PMID (29059438)
Authors 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 Journal of the National Cancer Institute
Vol 109
Issue 11
Date 2017 11 01
URL
Abstract Text 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.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.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] m 3 vs 298 [312] m 3 , P = .001, n = 4).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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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
ATM A220V missense no effect - predicted ATM A220V does not lie within any known functional domains of the Atm protein (UniProt.org). A220V increases cell viability and proliferation in the presence of radiation to the same extent as wild-type Atm (PMID: 29059438) and therefore, is predicted to have no effect on Atm protein function.
ATM A59S missense loss of function - predicted ATM A59S does not lie within any known functional domains of the Atm protein (UniProt.org). A59S is predicted to confer a loss of function to the Atm protein, as demonstrated by increased radiosensitivity of cultured cells, as compared to Atm wild-type (PMID: 29059438).
ATM H2038Y missense loss of function - predicted ATM H2038Y lies within the FAT domain of the Atm protein (UniProt.org). H2038Y is predicted to confer a loss of function to the Atm protein, as demonstrated by increased radiosensitivity of cultured cells, as compared to Atm wild-type (PMID: 29059438).
ATM K2749I missense loss of function - predicted ATM K2749I lies within the PI3K/PI4K domain of the Atm protein (UniProt.org). K2749I is predicted to confer a loss of function to the Atm protein, as demonstrated by increased radiosensitivity of cultured cells, as compared to Atm wild-type (PMID: 29059438).
ATM L1874F missense loss of function - predicted ATM L1874F does not lie within any known functional domains of the Atm protein (UniProt.org). L1874F is predicted to confer a loss of function to the Atm protein, as demonstrated by increased radiosensitivity of cultured cells, as compared to Atm wild-type (PMID: 29059438).
ATM L1956H missense loss of function - predicted ATM L1956H lies within the FAT domain of the Atm protein (UniProt.org). L1956H is predicted to confer a loss of function to the Atm protein, as demonstrated by increased radiosensitivity of cultured cells, as compared to Atm wild-type (PMID: 29059438).
ATM L581V missense no effect - predicted ATM L581V does not lie within any known functional domains of the Atm protein (UniProt.org). L581V increases cell viability and proliferation in the presence of radiation to the same extent as wild-type Atm (PMID: 29059438) and therefore, is predicted to have no effect on Atm protein function.
ATM N1650S missense unknown ATM N1650S does not lie within any known functional domains of the Atm protein (UniProt.org). N1650S results in impaired Atm phosphorylation of Tp53 and Chek2 in cultured cells (PMID: 12969974) but in another study leads to increased cell viability and proliferation in the presence of radiation to the same extent as wild-type Atm (PMID: 29059438), and therefore, its effect on Atm protein function is unknown.
ATM P604S missense loss of function - predicted ATM P604S does not lie within any known functional domains of the Atm protein (UniProt.org). P604S is predicted to confer a loss of function to the Atm protein, as demonstrated by increased radiosensitivity of cultured cells, as compared to Atm wild-type (PMID: 29059438).
ATM P960H missense loss of function - predicted ATM P960H does not lie within any known functional domains of the Atm protein (UniProt.org). P960H is predicted to confer a loss of function to the Atm protein, as demonstrated by increased radiosensitivity of cultured cells, as compared to Atm wild-type (PMID: 29059438).
ATM R2691C missense loss of function - predicted ATM R2691C does not lie within any known functional domains of the Atm protein (UniProt.org). R2691C is predicted to confer a loss of function to the Atm protein, as demonstrated by increased radiosensitivity of cultured cells, as compared to Atm wild-type (PMID: 29059438), and is predicted to impair the kinase activity of Atm by structural modeling (PMID: 21993670).
ATM R45Q missense no effect - predicted ATM R45Q does not lie within any known functional domains of the Atm protein (UniProt.org). R45Q increases cell viability and proliferation in the presence of radiation to the same extent as wild-type Atm (PMID: 29059438) and therefore, is predicted to have no effect on Atm protein function.
ATM S1455R missense loss of function ATM S1455R does not lie within any known functional domains of the Atm protein (UniProt.org). S1455R confers a loss of function to the Atm protein as demonstrated by impaired phosphorylation of p53 and Chek2 in cultured cells (PMID: 12969974) and increased radiosensitivity of cultured cells, as compared to Atm wild-type (PMID: 29059438).
ATM S2707C missense no effect - predicted ATM S2707C does not lie within any known functional domains of the Atm protein (UniProt.org). S2707C increases cell viability and proliferation in the presence of radiation to the same extent as wild-type Atm (PMID: 29059438) and therefore, is predicted to have no effect on Atm protein function.
ATM S824F missense loss of function - predicted ATM S824F does not lie within any known functional domains of the Atm protein (UniProt.org). S824F is predicted to confer a loss of function to the Atm protein, as demonstrated by increased radiosensitivity of cultured cells, as compared to Atm wild-type (PMID: 29059438).
ATM T2031I missense no effect - predicted ATM T2031I lies within the FAT domain of the Atm protein (UniProt.org). T2031I increases cell viability and proliferation in the presence of radiation to the same extent as wild-type Atm (PMID: 29059438) and therefore, is predicted to have no effect on Atm protein function.
ATM V1841I missense no effect - predicted ATM V1841I does not lie within any known functional domains of the Atm protein (UniProt.org). V1841I increases cell viability and proliferation in the presence of radiation to the same extent as wild-type Atm (PMID: 29059438) and therefore, is predicted to have no effect on Atm protein function.
ATM V519I missense loss of function - predicted ATM V519I does not lie within any known functional domains of the Atm protein (UniProt.org). V519I is predicted to confer a loss of function to the Atm protein, as demonstrated by increased radiosensitivity of cultured cells, as compared to Atm wild-type (PMID: 29059438).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ATM S1455R neuroblastoma sensitive Olaparib Preclinical - Cell culture Actionable In a preclinical study, Lynparza (olaparib) treatment of neuroblastoma cells in culture, transfected with Atm S1455R, resulted in decreased cell viability as compared to cells carrying wild-type Atm (PMID: 29059438). 29059438
ATM V519I neuroblastoma sensitive Olaparib Preclinical - Cell culture Actionable In a preclinical study, Lynparza (olaparib) treatment of neuroblastoma cells in culture, transfected with Atm V519I, resulted in decreased cell viability as compared to cells carrying wild-type Atm (PMID: 29059438). 29059438
ATM P604S neuroblastoma sensitive Olaparib Preclinical - Cell culture Actionable In a preclinical study, Lynparza (olaparib) treatment of neuroblastoma cells in culture, transfected with Atm P604S, resulted in decreased cell viability as compared to cells carrying wild-type Atm (PMID: 29059438). 29059438
ATM L1874F neuroblastoma sensitive Olaparib Preclinical - Cell culture Actionable In a preclinical study, Lynparza (olaparib) treatment of neuroblastoma cells in culture, transfected with Atm L1874F, resulted in decreased cell viability as compared to cells carrying wild-type Atm (PMID: 29059438). 29059438
ATM K2749I neuroblastoma sensitive Olaparib Preclinical - Cell culture Actionable In a preclinical study, Lynparza (olaparib) treatment of neuroblastoma cells in culture, transfected with Atm K2749I, resulted in decreased cell viability as compared to cells carrying wild-type Atm (PMID: 29059438). 29059438
ATM A59S neuroblastoma sensitive Olaparib Preclinical - Cell culture Actionable In a preclinical study, Lynparza (olaparib) treatment of neuroblastoma cells in culture, transfected with Atm A59S, resulted in decreased cell viability as compared to cells carrying wild-type Atm (PMID: 29059438). 29059438
ATM L1956H neuroblastoma no benefit Olaparib Preclinical - Cell culture Actionable In a preclinical study, Lynparza (olaparib) treatment of neuroblastoma cells in culture, transfected with Atm L1956H, resulted in similar cell viability levels as cells carrying wild-type Atm (PMID: 29059438). 29059438
ATM P960H neuroblastoma sensitive Olaparib Preclinical - Cell culture Actionable In a preclinical study, Lynparza (olaparib) treatment of neuroblastoma cells in culture, transfected with Atm P960H, resulted in decreased cell viability as compared to cells carrying wild-type Atm (PMID: 29059438). 29059438
ATM V1841I neuroblastoma sensitive Olaparib Preclinical - Cell culture Actionable In a preclinical study, Lynparza (olaparib) treatment of neuroblastoma cells in culture, transfected with Atm V1841I, resulted in decreased cell viability as compared to cells carrying wild-type Atm (PMID: 29059438). 29059438
ATM S824F neuroblastoma sensitive Olaparib Preclinical - Cell culture Actionable In a preclinical study, Lynparza (olaparib) treatment of neuroblastoma cells in culture, transfected with Atm S824F, resulted in decreased cell viability as compared to cells carrying wild-type Atm (PMID: 29059438). 29059438
ATM H2038Y neuroblastoma sensitive Olaparib Preclinical - Cell culture Actionable In a preclinical study, Lynparza (olaparib) treatment of neuroblastoma cells in culture, transfected with Atm H2038Y, resulted in decreased cell viability as compared to cells carrying wild-type Atm (PMID: 29059438). 29059438
ATM R2691C neuroblastoma no benefit Olaparib Preclinical - Cell culture Actionable In a preclinical study, Lynparza (olaparib) treatment of neuroblastoma cells in culture, transfected with Atm R2691C, resulted in similar cell viability levels as cells carrying wild-type Atm (PMID: 29059438). 29059438