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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 Vol Issue Date Pages Journal Short Title
Journal of the National Cancer Institute 109 11 2017 11 01 J Natl Cancer Inst
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 restores cell viability of ATM-deficient cells upon irradiation in culture (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 results in impaired ability to rescue survival of ATM-deficient cells upon irradiation in culture (PMID: 29059438), and therefore, is predicted to lead to a loss of Atm protein function.
ATM H2038Y missense loss of function - predicted ATM H2038Y lies within the FAT domain of the Atm protein (UniProt.org). H2038Y results in impaired ability to rescue survival of ATM-deficient cells upon irradiation in culture (PMID: 29059438), and therefore, is predicted to lead to a loss of Atm protein function.
ATM K2749I missense loss of function - predicted ATM K2749I lies within the PI3K/PI4K domain of the Atm protein (UniProt.org). K2749I results in decreased ability to rescue survival of ATM-deficient cells upon irradiation in culture (PMID: 29059438), and therefore, is predicted to lead to a loss of Atm protein function.
ATM L1874F missense loss of function - predicted ATM L1874F does not lie within any known functional domains of the Atm protein (UniProt.org). L1874F results in impaired ability to rescue survival of ATM-deficient cells upon irradiation in culture (PMID: 29059438), and therefore, is predicted to lead to a loss of Atm protein function.
ATM L1956H missense loss of function - predicted ATM L1956H lies within the FAT domain of the Atm protein (UniProt.org). L1956H results in impaired ability to rescue survival of ATM-deficient cells upon irradiation in culture (PMID: 29059438), and therefore, is predicted to lead to a loss of Atm protein function.
ATM L581V missense no effect - predicted ATM L581V does not lie within any known functional domains of the Atm protein (UniProt.org). L581V restores cell viability of ATM-deficient cells upon irradiation in culture (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 restores cell viability of ATM-deficient cells upon irradiation in culture (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 retains Atm expression and phosphorylation in a patient sample (PMID: 36555667) but results in impaired ability to rescue survival of ATM-deficient cells upon irradiation or PARP inhibitor treatment in culture (PMID: 29059438) and therefore, is predicted to lead to a loss of Atm protein function.
ATM P960H missense loss of function - predicted ATM P960H does not lie within any known functional domains of the Atm protein (UniProt.org). P960H results in impaired ability to rescue survival of ATM-deficient cells upon irradiation in culture (PMID: 29059438), and therefore, is predicted to lead to a loss of Atm protein function.
ATM R2691C missense loss of function - predicted ATM R2691C does not lie within any known functional domains of the Atm protein (UniProt.org). R2691C results in impaired ability to rescue survival of ATM-deficient cells upon irradiation in culture (PMID: 29059438), and via structural modeling, demonstrates potential for impaired kinase activity of Atm (PMID: 21993670), and therefore, is predicted to lead to a loss of Atm protein function.
ATM R45Q missense no effect - predicted ATM R45Q does not lie within any known functional domains of the Atm protein (UniProt.org). R45Q restores cell viability of ATM-deficient cells upon irradiation in culture (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 partial inability to rescue survival of ATM-deficient cells upon irradiation in culture (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 restores cell viability of ATM-deficient cells upon irradiation in culture (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 results in impaired ability to rescue survival of ATM-deficient cells upon irradiation in culture (PMID: 29059438), and therefore, is predicted to lead to a loss of Atm protein function.
ATM T2031I missense no effect - predicted ATM T2031I lies within the FAT domain of the Atm protein (UniProt.org). T2031I restores cell viability of ATM-deficient cells upon irradiation in culture (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 restores viability of ATM-deficient cells upon irradiation in culture (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 results in impaired ability to rescue survival of ATM-deficient cells upon irradiation in culture (PMID: 29059438), and therefore, is predicted to lead to a loss of Atm protein function.
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ATM V519I neuroblastoma sensitive Olaparib Preclinical - Cell culture Actionable In a preclinical study, Lynparza (olaparib) treatment decreased viability of transformed neuroblastoma cells expressing ATM V519I in culture (PMID: 29059438). 29059438
ATM S1455R neuroblastoma sensitive Olaparib Preclinical - Cell culture Actionable In a preclinical study, Lynparza (olaparib) treatment decreased viability of transformed neuroblastoma cells expressing ATM S1455R in culture (PMID: 29059438). 29059438
ATM L1956H neuroblastoma no benefit Olaparib Preclinical - Cell culture Actionable In a preclinical study, Lynparza (olaparib) treatment of transformed neuroblastoma cells expressing ATM L1956H resulted in similar cell viability levels to wild-type Atm in culture (PMID: 29059438). 29059438
ATM S824F neuroblastoma sensitive Olaparib Preclinical - Cell culture Actionable In a preclinical study, Lynparza (olaparib) treatment decreased viability of transformed neuroblastoma cells expressing ATM S824F in culture (PMID: 29059438). 29059438
ATM P604S neuroblastoma sensitive Olaparib Preclinical - Cell culture Actionable In a preclinical study, Lynparza (olaparib) treatment decreased viability of transformed neuroblastoma cells expressing ATM P604S in culture (PMID: 29059438). 29059438
ATM H2038Y neuroblastoma sensitive Olaparib Preclinical - Cell culture Actionable In a preclinical study, Lynparza (olaparib) treatment decreased viability of transformed neuroblastoma cells expressing ATM H2038Y in culture (PMID: 29059438). 29059438
ATM P960H neuroblastoma sensitive Olaparib Preclinical - Cell culture Actionable In a preclinical study, Lynparza (olaparib) treatment decreased viability of transformed neuroblastoma cells expressing ATM P960H in culture (PMID: 29059438). 29059438
ATM R2691C neuroblastoma no benefit Olaparib Preclinical - Cell culture Actionable In a preclinical study, Lynparza (olaparib) treatment of transformed neuroblastoma cells expressing ATM R2691C resulted in similar cell viability levels to wild-type Atm in culture (PMID: 29059438). 29059438
ATM K2749I neuroblastoma sensitive Olaparib Preclinical - Cell culture Actionable In a preclinical study, Lynparza (olaparib) treatment decreased viability of transformed neuroblastoma cells expressing ATM K2749I in culture (PMID: 29059438). 29059438
ATM L1874F neuroblastoma sensitive Olaparib Preclinical - Cell culture Actionable In a preclinical study, Lynparza (olaparib) treatment decreased viability of transformed neuroblastoma cells expressing ATM L1874F in culture (PMID: 29059438). 29059438
ATM V1841I neuroblastoma sensitive Olaparib Preclinical - Cell culture Actionable In a preclinical study, Lynparza (olaparib) treatment decreased viability of transformed neuroblastoma cells expressing ATM V1841I in culture (PMID: 29059438). 29059438
ATM A59S neuroblastoma sensitive Olaparib Preclinical - Cell culture Actionable In a preclinical study, Lynparza (olaparib) treatment decreased viability of transformed neuroblastoma cells expressing ATM A59S in culture (PMID: 29059438). 29059438