Reference Detail

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
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 partial inability 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 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 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 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 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 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 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 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 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 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 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 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