Evidence map›Paper›PMID 39427557›Full record

ArticleGynecologic oncology2024

ATR inhibition increases reliance on PARP-mediated DNA repair revealing an improved therapeutic strategy for cervical cancer.

Sugantha Priya Elayapillai, Samrita Dogra, James Lausen, Madison Parker, Amy Kennedy, Doris M Benbrook, Katherine M Moxley, Bethany N Hannafon

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Gynecologic oncology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.

0numbers the graph read from it
0cells of the map it votes in
7citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

7 citing papers in PubMed.

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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

8 authors.

Sugantha Priya ElayapillaiDepartment of Obstetrics and Gynecology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA. Electronic address: Suganthapriya-Elayapillai@ouhsc.edu.
Samrita DograDepartment of Obstetrics and Gynecology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA. Electronic address: Samrita-Dogra@ouhsc.edu.
James LausenDepartment of Obstetrics and Gynecology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA. Electronic address: James-Lausen@ouhsc.edu.
Madison ParkerDepartment of Obstetrics and Gynecology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
Amy KennedyDepartment of Obstetrics and Gynecology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
Doris M BenbrookDepartment of Obstetrics and Gynecology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA. Electronic address: Doris-Benbrook@ouhsc.edu.
Katherine M MoxleyOklahoma Cancer Specialists and Research Institute, Tulsa, OK 74164, USA. Electronic address: Katherine.moxley@ocsri.org.
Bethany N HannafonDepartment of Obstetrics and Gynecology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA. Electronic address: Bethany-Hannafon@ouhsc.edu.

Funding

Tissue Pathology Shared ResourceP30CA225520 · NCI · UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR · PI Michael S. Businelle · 2018 to 2026
$27.1M
TUMOR RESISTANCE MECHANISMS TO ANTI-VEGF THERAPY IN PROSTATE CANCER (Sukyung Woo)P20GM103639 · NIGMS · UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR · PI HANNAFON, BETHANY · 2012 to 2022
$21.3M
Mentoring Translational Cancer Research in OklahomaP30GM154635 · NIGMS · UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR · PI Danny N. Dhanasekaran · 2024 to 2026
$4.3M
Axio SWhole slide scanning fluorescence and bright field microscopy with image analysis (ZEISScan.Z1)S10OD026744 · OD · UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR · PI FUNG, KAR-MING ARMIN · 2019 to 2019
$187k
NCI NIH HHS P30 CA225520NIGMS NIH HHS P20 GM103639NIGMS NIH HHS P30 GM154635NIH HHS S10 OD026744
6 · The paper itself

Abstract

objectiveCervical cancer results from persistent infection with high-risk human papillomavirus (HR-HPV) and the expression of E6 and E7 oncoproteins. E6 and E7 compromise the activity of p53 and Rb, the G1-S cell cycle checkpoint, and ATM-mediated DNA damage repair (DDR), which in turn increases reliance on ATR- and PARP-mediated DDR at the G2 cell cycle checkpoint. This study aimed to determine the effects of an ATR inhibitor (ATRi, AZD6738) and a PARP-inhibitor (PARPi, AZD2281) on HR-HPV+ cervical cancer cell lines.

methodsThe effects of ATRi and PARPi, alone and in combination, on metabolic viability, cell cycle arrest, apoptosis, and DDR pathways in cervical cancer cell lines were evaluated in vitro, and the in vivo tumor response was evaluated using a xenograft model.

resultsCervical cancer cells were sensitive to ATRi and PARPi monotherapy. The combination therapy was only synergistic in reducing metabolic viability when exposed to ATRi first, followed by PARPi, owing to ATRi-mediated upregulation of PARP expression. Combination of ATRi and PARPi induced G2 cell cycle arrest and apoptosis. PARPi induced DNA damage and γH2AX phosphorylation, which was further increased by ATRi treatment. However, PARPi-induced Rad51 foci formation was reduced by ATRi treatment, suggesting the inhibition of homologous recombination repair. ATRi significantly reduced cervical cancer xenograft tumor growth and was not affected by simultaneous PARPi treatment at the doses studied.

conclusionsOur findings show that ATRi increased reliance on PARP for metabolic viability, the combination of ATRi and PARPi induced synthetic lethality in cervical cancer in vitro, and reduced tumor burden in vivo.

Indexed as

Ataxia Telangiectasia Mutated ProteinsDNA RepairPoly(ADP-ribose) Polymerase InhibitorsUterine Cervical NeoplasmsXenograft Model Antitumor AssaysAnimalsAntineoplastic Combined Chemotherapy ProtocolsApoptosisCell Line, TumorFemaleHumansIndolesMiceMice, NudeMorpholinesPhthalazinesAtaxia Telangiectasia Mutated ProteinsATR protein, humanceralasertibIndolesMorpholinesPhthalazinesPoly(ADP-ribose) Polymerase InhibitorsPyrimidinesSulfonamidesATRCervical cancerDNA damage repairHPV-related cancerPARP

Identifiers

PMID39427557
PMCPMC11975412

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.