The brain-penetrant clinical ATM inhibitor AZD1390 radiosensitizes and improves survival of preclinical brain tumor models

Durant, Stephen T.; Zheng, Lichun; Wang, Yingchun; Chen, Kan; Zhang, Lingli; Zhang, Tianwei; Yang, Zhenfan; Riches, Lucy C.; Trinidad, Antonio G.; Fok, Jacqueline H. L.; Hunt, Thomas A.; Pike, Kurt G.; Wilson, Joanne; Smith, Aaron; Colclough, Nicola; Reddy, Venkatesh Pilla; Sykes, Andrew J; Janefeldt, Annika; Johnström, Peter; Varnäs, Katarina; Takano, Akihiro; Ling, Stephanie; Orme, Jonathan P.; Stott, Jonathan; Roberts, Caroline G.P.; Barrett, Ian P.; Jones, Gemma N.; Roudier, Martine P.; Pierce, Andrew J.; Allen, Joseph D.; Kahn, Jenna; Sule, Amrita; Karlin, Jeremy; Cronin, Anna; Chapman, Melissa; Valerie, Kristoffer; Illingworth, Ruth; Pass, Martin

doi:10.1126/sciadv.aat1719

Cited by 237 publications

(230 citation statements)

References 42 publications

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“…As shown in Fig. 2B, incubation of cells with arsenite alone increased the level of PAR sensor fluorescence, which increased further with concurrent ATM inhibition (AZD1390) (Durant et al, 2018). The level of PARylation observed with ATM depletion was reduced by veliparib treatment, as expected, since the majority of PAR formed in cells is generated by PARP1 and PARP2 (Gupte et al, 2017).…”

Section: Protein Aggregation Observed With Atm Depletion Is Dependentsupporting

confidence: 70%

Poly-ADP-ribosylation drives loss of protein homeostasis in ATM and Mre11 deficiency

Lee

Ryu

Ender

et al. 2020

Preprint

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Loss of the ataxia-telangiectasia mutated (ATM) kinase causes cerebellum-specific neurodegeneration in humans. We previously demonstrated that deficiency in ATM activation via oxidative stress generates high levels of insoluble protein aggregates in human cells, reminiscent of protein dysfunction in common neurodegenerative disorders. Here we show that this process is driven by poly-ADP-ribose polymerases (PARPs) and that the insoluble protein species arise from intrinsically disordered proteins associating with PAR-associated genomic sites in ATM-deficient cells. The lesions implicated in this process are single-strand DNA breaks dependent on reactive oxygen species, transcription, and R-loops. Human cells expressing Mre11 A-T-like disorder (ATLD) mutants also show PARP-dependent aggregation identical to that of ATM deficiency. Lastly, analysis of A-T patient cerebellum samples shows widespread protein aggregation as well as loss of proteins known to be critical in human spinocerebellar ataxias. These results provide a new hypothesis for loss of protein integrity and cerebellum function in A-T.

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Section: Protein Aggregation Observed With Atm Depletion Is Dependentsupporting

confidence: 70%

Poly-ADP-ribosylation drives loss of protein homeostasis in ATM and Mre11 deficiency

Lee

Ryu

Ender

et al. 2020

Preprint

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“…In both schedules olaparib was administered continually at 50 mg/kg. Previously published data demonstrates that HBCx-10 model is known to be sensitive to olaparib treatment alone and demonstrates regressions in combination with AZD0156 using schedule 1 (28). Using schedule 2 in this HBCx-10 model, olaparib alone induced regressions in one of 10 tumors, however in combination with AZD0156 tumor, regression was achieved in 3 of the 8 treated mice and additionally tumor stasis was seen in 4 of the remaining 5 mice (Fig.…”

Section: Azd0156 Improves the Response Of Olaparib Treatment In Patiementioning

confidence: 62%

“…Importantly, another potent ATM inhibitor under clinical evaluation, AZD1390 has been recently reported to radiosensitize preclinical brain tumor models inducing tumor regression and shows efficient blood-brain barrier penetration in vivo (28).…”

Section: Introductionmentioning

confidence: 99%

Pharmacology of the ATM Inhibitor AZD0156: Potentiation of Irradiation and Olaparib Responses Preclinically

Riches

Trinidad

Hughes

et al. 2020

Molecular Cancer Therapeutics

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117

107

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AZD0156 is a potent and selective, bioavailable inhibitor of ataxia-telangiectasia mutated (ATM) protein, a signaling kinase involved in the DNA damage response. We present preclinical data demonstrating abrogation of irradiation-induced ATM signaling by low doses of AZD0156, as measured by phosphorylation of ATM substrates. AZD0156 is a strong radiosensitizer in vitro, and using a lung xenograft model, we show that systemic delivery of AZD0156 enhances the tumor growth inhibitory effects of radiation treatment in vivo. Because ATM deficiency contributes to PARP inhibitor sensitivity, preclinically, we evaluated the effect of combining AZD0156 with the PARP inhibitor olaparib. Using ATM isogenic FaDu cells, we demonstrate that AZD0156 impedes the repair of olaparib-induced DNA damage, resulting in elevated DNA double-strand break signaling, cellcycle arrest, and apoptosis. Preclinically, AZD0156 potentiated the effects of olaparib across a panel of lung, gastric, and breast cancer cell lines in vitro, and improved the efficacy of olaparib in two patient-derived triple-negative breast cancer xenograft models. AZD0156 is currently being evaluated in phase I studies (NCT02588105).

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“…Because gastric cancer progression is typically accompanied by ATM activation, ATM inhibition with specific inhibitors could be a possible alternative therapeutic strategy. Highly selective small molecule ATM inhibitors such as AZD1390 are currently in the preclinical development stages (Durant et al 2018). Thus far, this drug has shown promising results in brain tumor models.…”

Section: Future Perspectivesmentioning

confidence: 99%

Helicobacter pylori infection induced genome instability and gastric cancer

Liu

Irfan

et al. 2020

GENOME INSTAB. DIS.

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Genome stability and integrity are constantly challenged by exogenous insults such as bacterial infections. When genome stability is perturbed, oncogenic transformation can ensue. Helicobacter pylori (H. pylori) infection is a driving factor of gastric cancer, which is the third leading cause of cancer-related mortality worldwide. Mechanistically, H. pylori infection drives inflammation and directly or indirectly induces DNA damage such as oxidative damage and double-strand breaks (DSBs) in host cells. In addition, the resulting genetic and/or epigenetic perturbations alter the choice of DNA repair pathways. These changes result in imprecise DNA repair, genomic instability as well as chromosomal aberrations that eventually lead to gastric carcinogenesis. In this review, we summarize the mechanisms how H. pylori infection cause DNA damage and alter the DNA damage response pathways in host cells. We highlight the relationship between H. pylori infection and genomic instability that can lead to gastric cancer and propose a potential strategy to interrupt gastric carcinogenesis.

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The brain-penetrant clinical ATM inhibitor AZD1390 radiosensitizes and improves survival of preclinical brain tumor models

Abstract: Preclinical data highlight AZD1390 as a potentially powerful new therapy to enhance brain tumor patient responses to radiotherapy.

Cited by 237 publications

References 42 publications

Poly-ADP-ribosylation drives loss of protein homeostasis in ATM and Mre11 deficiency

Poly-ADP-ribosylation drives loss of protein homeostasis in ATM and Mre11 deficiency

Pharmacology of the ATM Inhibitor AZD0156: Potentiation of Irradiation and Olaparib Responses Preclinically

Helicobacter pylori infection induced genome instability and gastric cancer

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