Ataxia Telangiectasia Mutated and Rad3 Related (ATR) Protein Kinase Inhibition Is Synthetically Lethal in XRCC1 Deficient Ovarian Cancer Cells

Sultana, Rebeka; Abdel-Fatah, Tarek M.A.; Perry, Christina; Moseley, Paul M.; Nada, Albarakti; Mohan, Vivek; Seedhouse, Claire; Chan, Stephen Y.; Madhusudan, Srinivasan

doi:10.1371/journal.pone.0057098

Cited by 76 publications

(58 citation statements)

References 35 publications

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“…Of note, these studies demonstrated that loss of excision repair cross-complementation group 1 protein (ERCC1), which functions in the repair of bulky DNA adducts, DSBs, and interstrand cross-links (77), was a significant SL interaction with ATR and CHK1 inhibition. Similar SL interactions were observed between ATR inhibition and loss of another repair gene known as XRCC1, which plays a role base excision repair (78) and with ATM deficiency (34).…”

Section: Strategies For Clinical Development: Past and Presentsupporting

confidence: 56%

Achieving Precision Death with Cell-Cycle Inhibitors that Target DNA Replication and Repair

Lin

McNeely

Beckmann

2017

Clinical Cancer Research

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All cancers are characterized by defects in the systems that ensure strict control of the cell cycle in normal tissues. The consequent excess tissue growth can be countered by drugs that halt cell division, and, indeed, the majority of chemotherapeutics developed during the last century work by disrupting processes essential for the cell cycle, particularly DNA synthesis, DNA replication, and chromatid segregation. In certain contexts, the efficacy of these classes of drugs can be impressive, but because they indiscriminately block the cell cycle of all actively dividing cells, their side effects severely constrain the dose and duration with which they can be administered, allowing both normal and malignant cells to escape complete growth arrest. Recent progress in understanding how cancers lose control of the cell cycle, coupled with comprehensive genomic profiling of human tumor biopsies, has shown that many cancers have mutations affecting various regulators and checkpoints that impinge on the core cell-cycle machinery. These defects introduce unique vulnerabilities that can be exploited by a next generation of drugs that promise improved therapeutic windows in patients whose tumors bear particular genomic aberrations, permitting increased dose intensity and efficacy. These developments, coupled with the success of new drugs targeting cell-cycle regulators, have led to a resurgence of interest in cellcycle inhibitors. This review in particular focuses on the newer strategies that may facilitate better therapeutic targeting of drugs that inhibit the various components that safeguard the fidelity of the fundamental processes of DNA replication and repair. Clin Cancer Res; 23(13); 3232-40. Ó2017 AACR.

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Section: Strategies For Clinical Development: Past and Presentsupporting

confidence: 56%

Achieving Precision Death with Cell-Cycle Inhibitors that Target DNA Replication and Repair

Lin

McNeely

Beckmann

2017

Clinical Cancer Research

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“…The ATR-mediated DNA damage response not only activates cell cycle checkpoints but also regulates replication and different tolerance pathways, and ATR is a vital kinase for protecting the genome against DNA damage that blocks replication. Inhibiting ATR has the potential to protect against UVB-induced carcinogenesis (Conney et al, 2007) and is growing as a potential sensitizer of chemotherapy or radiation, with selective killing of p53-deficient cancer cells (Reaper et al, 2011;Peasland et al, 2011;Prevo et al, 2012;Sultana et al, 2013). Thus, knowledge of the ATR-mediated DNA damage response can also aid in the design of more efficient cancer treatment protocols.…”

Section: Discussionmentioning

confidence: 99%

ATR suppresses apoptosis after UVB light by controlling both translesion synthesis and alternative tolerance pathways

Andrade-Lima

Andrade

Menck

2014

Journal of Cell Science

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Ultraviolet (UV) light can stall replication forks owing to the formation of bulky lesions in the DNA. Replication across these blocking lesions occurs through translesion DNA synthesis, and cells activate the ATR damage responses to UV. However, it remains unclear whether lesion bypass requires the replication checkpoint because ATR is not necessary for PCNA ubiquitylation. We observed that ATR knockdown by siRNA increased replication stress and promoted early induction of apoptosis following UVB irradiation in SV40-immortalized human cells, including cells from XP-V and XP-C patients. XP-V cells were further sensitized by the silencing, indicating that DNA polymerase g (Pol g) remains active despite ATR control. However, following UVB irradiation, ATR-depleted cells were unable to achieve mitosis, as would be expected after the loss of a DNA checkpoint control. Thus, ATR also regulates replication arrest recovery following UVB-induced damage, independently of Pol g, in SV40-immortalized cell lines. The ATR-mediated DNA damage response regulates replication and different tolerance pathways, and in these cells, ATR depletion induces replication catastrophe, which contributes to explain the potential of ATR inhibition to protect against UVB-induced carcinogenesis.

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“…Furthermore, the intrinsic therapeutic potential of ATR-pathway inhibition is also very promising. ATR or CHEK1 inhibition in ERCC1-deficient cells causes failure to complete cell cycle transitions even after drug removal, suggesting that ATR pathway targeted drugs may offer particular utility in cancers with reduced ATR pathway function by causing synthetic lethality [18–20]. As such, one could foresee therapeutic impact derived from modulation or inhibition of ATR specifically in the subset of endometrial cancer patients with defective DNA mismatch repair.…”

Section: Commentmentioning

confidence: 99%

Assessing the prognostic role of ATR mutation in endometrioid endometrial cancer: An NRG Oncology/Gynecologic Oncology Group study

Zighelboim

Ali

Lankes

et al. 2015

Gynecologic Oncology

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Objective We sought to validate the clinicopathologic implications and prognostic significance of ATR (ataxia telangiectasia mutated and Rad3-related) mutation in patients with endometrioid endometrial cancer and defective DNA mismatch repair enrolled in a cooperative group molecular staging study of endometrial cancer Methods After pathology review, only endometrioid tumors with high neoplastic cellularity (≥70%) and high quality DNA for molecular analyses were included. MSI (microsatellite instability) typing was performed and the target sequence in exon 10 of ATR was evaluated by direct sequencing in all MSI-high tumors. Associations between ATR mutations and clinicopathologic variables were assessed using contingency table tests. Differences in overall survival (OS) and disease-free survival (DFS) were evaluated by univariate analyses and multivariable Cox proportional hazard models. Results A total of 475 eligible cases were identified. Of 368 MSI+ cases, the sequence of interest could be successfully genotyped in 357 cases. ATR mutations were exclusively identified in 46 tumors with high level microsatellite instability (MSI+) (12.9%, p<0.001) and were associated with higher tumor grade (p=0.001). ATR mutations were not associated with OS (HR 1.16; 95% CI, 0.58–2.32; p=0.68) or DFS (HR 0.61; 95%CI, 0.25–1.50; p=0.28). Conclusion Truncating mutations in exon 10 of ATR occur exclusively in tumors with evidence of defective DNA mismatch repair. We were not able to confirm the prognostic value of these mutations in patients with endometrioid endometrial cancer.

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Ataxia Telangiectasia Mutated and Rad3 Related (ATR) Protein Kinase Inhibition Is Synthetically Lethal in XRCC1 Deficient Ovarian Cancer Cells

Cited by 76 publications

References 35 publications

Achieving Precision Death with Cell-Cycle Inhibitors that Target DNA Replication and Repair

Achieving Precision Death with Cell-Cycle Inhibitors that Target DNA Replication and Repair

ATR suppresses apoptosis after UVB light by controlling both translesion synthesis and alternative tolerance pathways

Assessing the prognostic role of ATR mutation in endometrioid endometrial cancer: An NRG Oncology/Gynecologic Oncology Group study

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