Targeting ATR in cancer

Lecona, Emilio; Fernández-Capetillo, Óscar

doi:10.1038/s41568-018-0034-3

Cited by 286 publications

(257 citation statements)

References 149 publications

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“…3A). In DNA damage repair pathways, the ATM/ATR could be activated by many partners [14,15]. WEE1 inhibition might reduce positive controller such as TIP60, ETAA1, and TopBP1, or enhance negative controller like histone linker 1.2.…”

Section: Atm/atr Activation Correlates With Sensitivity Of Btc Cells mentioning

confidence: 99%

Inhibition of ATR Increases the Sensitivity to WEE1 Inhibitor in Biliary Tract Cancer

et al. 2020

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Original ArticlePurpose Currently, the DNA damage response (DDR) pathway represents a key target for new cancer drug development. Advanced biliary tract cancer (BTC) has a poor prognosis because of the lack of efficacious treatment options. Although DNA repair pathway alterations have been reported in many patients with BTC, little is known regarding the effects of DDR-targeted agents against BTC. Materials and MethodsIn this study, nine BTC cell lines were exposed to the WEE1 inhibitor (AZD1775). In vitro, MTT assay, colony-forming assay, cell cycle analysis, phospho-histone H3 staining assay, Transwell migration assay, and western blot were performed. Then, to enhance the antitumor effect of AZD1775, the combination treatment of WEE1 inhibitor and ataxia telangiectasia mutated and Rad3 related (ATR) inhibitor (AZD6738) was conducted using MTT assay and comet assay. Finally, HuCCT-1 and SNU2670 xenograft models were established to confirm the anti-tumor effect of AZD1775 alone. Furthermore, the combination treatment was also evaluated in SNU2670 xenograft models. ResultsAZD1775 blocked the phosphorylation of CDC2 and CDC25C in all cell lines, but significantly increased apoptosis and S phase arrest in sensitive cells. However, increased p-ATR and phosphorylated ataxia telangiectasia mutated levels were observed in less sensitive cells. In addition, in vitro and in vivo data illustrated that AZD1775 combined with AZD6738 exerted more potent anti-tumor effects than either drug alone. Although WEE1 inhibition has promising anti-tumor effects in some BTC cells, the addition of ATR inhibitors could enhance its efficacy. ConclusionTaken together, this study supports further clinical development of DDR-targeted strategies as monotherapy or combination regimens for BTC.

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Section: Atm/atr Activation Correlates With Sensitivity Of Btc Cells mentioning

confidence: 99%

Inhibition of ATR Increases the Sensitivity to WEE1 Inhibitor in Biliary Tract Cancer

et al. 2020

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“…This could help to explain why ETAA1 deficiency in mice manifests with partially penetrant lethality during embryogenesis and defective clonal expansion of T lymphocytes (Miosge et al, 2017), processes entailing rapid cell proliferation where efficient ETAA1-mediated G2/M checkpoint control may be instrumental in suppressing gross chromosomal instability. Targeted inhibition of ETAA1 functionality might thus unmask a selective vulnerability in highly proliferative malignant cells that generally experience deregulated control of cell cycle progression and elevated replicative stress, providing potential opportunities for the continued evolution of promising therapeutic strategies targeting ATR signaling in cancer (Lecona and Fernandez-Capetillo, 2018).…”

Section: Aad Phosphorylation Is Critical For Etaa1-dependent Suppressmentioning

confidence: 99%

Regulation of ETAA1-mediated ATR activation couples DNA replication fidelity and genome stability

Achuthankutty

Thakur

Haahr

et al. 2019

Journal of Cell Biology

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The ATR kinase is a master regulator of the cellular response to DNA replication stress. Activation of ATR relies on dual pathways involving the TopBP1 and ETAA1 proteins, both of which harbor ATR-activating domains (AADs). However, the exact contribution of the recently discovered ETAA1 pathway to ATR signaling in different contexts remains poorly understood. Here, using an unbiased CRISPR-Cas9–based genome-scale screen, we show that the ATR-stimulating function of ETAA1 becomes indispensable for cell fitness and chromosome stability when the fidelity of DNA replication is compromised. We demonstrate that the ATR-activating potential of ETAA1 is controlled by cell cycle– and replication stress–dependent phosphorylation of highly conserved residues within its AAD, and that the stimulatory impact of these modifications is required for the ability of ETAA1 to prevent mitotic chromosome abnormalities following replicative stress. Our findings suggest an important role of ETAA1 in protecting against genome instability arising from incompletely duplicated DNA via regulatory control of its ATR-stimulating potential.

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“…These critical functions of ATR in coordinating the response to replication stress has made it an attractive therapeutic target in oncology given the observation that tumors often display signs of replication stress (Gaillard et al 2015;Lecona and Fernandez-Capetillo 2018 (Reaper et al 2011;Morgado-Palacin et al 2016;Nieto-Soler et al 2016;Williamson et al 2016;Buisson et al 2017;Green et al 2017;Jones et al 2017). Hustedt al., We reasoned that the unbiased identification of genes promoting viability following ATR inhibition would be useful for two purposes.…”

Section: Introductionmentioning

confidence: 99%

A consensus set of genetic vulnerabilities to ATR inhibition

Hustedt

Álvarez-Quilón

McEwan

et al. 2019

Preprint

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The response to DNA replication stress in eukaryotes is under the control of the ataxia-telangiectasia and Rad3-related (ATR) kinase. ATR responds to single-stranded (ss) DNA to stabilize distressed DNA replication forks, modulate DNA replication firing and prevent cells with damaged DNA or incomplete DNA replication from entering into mitosis. Furthermore, inhibitors of ATR are currently in clinical development either as monotherapies or in combination with agents that perturb DNA replication. To gain a genetic view of the cellular pathways requiring ATR kinase function, we mapped genes whose mutation causes hypersensitivity to ATR inhibitors with genome-scale CRISPR/Cas9 screens. We delineate a consensus set of 117 genes enriched in DNA replication, DNA repair and cell cycle regulators that promote survival when ATR kinase activity is suppressed. We validate 14 genes from this set and report genes not previously described to modulate response to ATR inhibitors. In particular we found that the loss of the POLE3/POLE4 proteins, which are DNA polymerase e accessory subunits, results in marked hypersensitivity to ATR inhibition. We anticipate that this 117-gene set will be useful for the identification of genes involved in the regulation of genome integrity, the characterization of new biological processes involving ATR, and may reveal biomarkers of ATR inhibitor response in the clinic.

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Targeting ATR in cancer

Cited by 286 publications

References 149 publications

Inhibition of ATR Increases the Sensitivity to WEE1 Inhibitor in Biliary Tract Cancer

Inhibition of ATR Increases the Sensitivity to WEE1 Inhibitor in Biliary Tract Cancer

Regulation of ETAA1-mediated ATR activation couples DNA replication fidelity and genome stability

A consensus set of genetic vulnerabilities to ATR inhibition

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