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ATM Deficiency Generating Genomic Instability Sensitizes Pancreatic Ductal Adenocarcinoma Cells to Therapy-Induced DNA Damage

Overview of attention for article published in Cancer Research, October 2017
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Title
ATM Deficiency Generating Genomic Instability Sensitizes Pancreatic Ductal Adenocarcinoma Cells to Therapy-Induced DNA Damage
Published in
Cancer Research, October 2017
DOI 10.1158/0008-5472.can-17-0634
Pubmed ID
Authors

Lukas Perkhofer, Anna Schmitt, Maria Carolina Romero Carrasco, Michaela Ihle, Stephanie Hampp, Dietrich Alexander Ruess, Elisabeth Hessmann, Ronan Russell, André Lechel, Ninel Azoitei, Qiong Lin, Stefan Liebau, Meike Hohwieler, Hanibal Bohnenberger, Marina Lesina, Hana Algül, Laura Gieldon, Evelin Schröck, Jochen Gaedcke, Martin Wagner, Lisa Wiesmüller, Bence Sipos, Thomas Seufferlein, Hans Christian Reinhardt, Pierre-Olivier Frappart, Alexander Kleger

Abstract

Pancreatic adenocarcinomas (PDAC) harbour recurrent functional mutations of the master DNA damage response kinase ATM which has been shown to accelerate tumorigenesis and epithelial-mesenchymal transition. To study how ATM deficiency affects genome integrity in this setting, we evaluated the molecular and functional effects of conditional Atm deletion in a mouse model of PDAC. ATM deficiency was associated with increased mitotic defects, recurrent genomic rearrangements and deregulated DNA integrity checkpoints, reminiscent of human PDAC. We hypothesized that altered genome integrity might allow synthetic lethality-based options for targeted therapeutic intervention. Supporting this possibility, we found that the PARP inhibitor olaparib or ATR inhibitors reduced the viability of PDAC cells in vitro and in vivo associated with a genotype-selective increase in apoptosis. Overall, our results offered a preclinical mechanistic rationale for the use of PARP and ATR inhibitors to improve treatment of ATM-mutant PDAC.

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Mendeley readers

Mendeley readers

The data shown below were compiled from readership statistics for 90 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Unknown 90 100%

Demographic breakdown

Readers by professional status Count As %
Researcher 17 19%
Student > Master 12 13%
Student > Ph. D. Student 11 12%
Student > Bachelor 6 7%
Other 5 6%
Other 10 11%
Unknown 29 32%
Readers by discipline Count As %
Biochemistry, Genetics and Molecular Biology 23 26%
Medicine and Dentistry 19 21%
Agricultural and Biological Sciences 10 11%
Social Sciences 3 3%
Immunology and Microbiology 2 2%
Other 2 2%
Unknown 31 34%
Attention Score in Context

Attention Score in Context

This research output has an Altmetric Attention Score of 2. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 16 October 2017.
All research outputs
#15,172,895
of 25,383,225 outputs
Outputs from Cancer Research
#14,366
of 19,140 outputs
Outputs of similar age
#172,836
of 332,415 outputs
Outputs of similar age from Cancer Research
#119
of 187 outputs
Altmetric has tracked 25,383,225 research outputs across all sources so far. This one is in the 38th percentile – i.e., 38% of other outputs scored the same or lower than it.
So far Altmetric has tracked 19,140 research outputs from this source. They typically receive more attention than average, with a mean Attention Score of 9.4. This one is in the 23rd percentile – i.e., 23% of its peers scored the same or lower than it.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 332,415 tracked outputs that were published within six weeks on either side of this one in any source. This one is in the 46th percentile – i.e., 46% of its contemporaries scored the same or lower than it.
We're also able to compare this research output to 187 others from the same source and published within six weeks on either side of this one. This one is in the 34th percentile – i.e., 34% of its contemporaries scored the same or lower than it.