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Gemcitabine and ATR inhibitors synergize to kill PDAC cells by blocking DNA damage response.

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Title: Gemcitabine and ATR inhibitors synergize to kill PDAC cells by blocking DNA damage response.
Authors: Höfer, Stefanie, Frasch, Larissa, Brajkovic, Sarah, Putzker, Kerstin, Lewis, Joe, Schürmann, Hendrik, Leone, Valentina, Sakhteman, Amirhossein, The, Matthew, Bayer, Florian P, Müller, Julian, Hamood, Firas, Siveke, Jens T, Reichert, Maximilian, Kuster, Bernhard
Source: Molecular Systems Biology; Mar2025, Vol. 21 Issue 3, p231-253, 23p
Subject Terms: DRUG synergism, PANCREATIC cancer, KINASE inhibitors, DNA damage, CHECKPOINT kinase 1, DNA repair
Abstract: The DNA-damaging agent Gemcitabine (GEM) is a first-line treatment for pancreatic cancer, but chemoresistance is frequently observed. Several clinical trials investigate the efficacy of GEM in combination with targeted drugs, including kinase inhibitors, but the experimental evidence for such rationale is often unclear. Here, we phenotypically screened 13 human pancreatic adenocarcinoma (PDAC) cell lines against GEM in combination with 146 clinical inhibitors and observed strong synergy for the ATR kinase inhibitor Elimusertib in most cell lines. Dose-dependent phosphoproteome profiling of four ATR inhibitors following DNA damage induction by GEM revealed a strong block of the DNA damage response pathway, including phosphorylated pS468 of CHEK1, as the underlying mechanism of drug synergy. The current work provides a strong rationale for why the combination of GEM and ATR inhibition may be useful for the treatment of PDAC patients and constitutes a rich phenotypic and molecular resource for further investigating effective drug combinations. Synopsis: Phosphoproteomics unveils the mode of action of clinical ATR inhibitors and explains their synergy with Gemcitabine in pancreatic cancer cells. Viability screening of 146 targeted drugs identified ATR kinase inhibitor Elimusertib to broadly synergize with Gemcitabine across 13 PDAC cell lines. Phosphoproteomics revealed strong DNA damage induction by Gemcitabine and simultaneous blockage of DNA repair pathways by ATR inhibition as mechanism of drug synergy. The mechanistic insights presented herein provide a molecular rationale for the clinical use of combined Gemcitabine and ATR inhibitors in PDAC patients. Phosphoproteomics unveils the mode of action of clinical ATR inhibitors and explains their synergy with Gemcitabine in pancreatic cancer cells. [ABSTRACT FROM AUTHOR]
Copyright of Molecular Systems Biology is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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  Data: Gemcitabine and ATR inhibitors synergize to kill PDAC cells by blocking DNA damage response.
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  Data: Molecular Systems Biology; Mar2025, Vol. 21 Issue 3, p231-253, 23p
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  Data: <searchLink fieldCode="DE" term="%22DRUG+synergism%22">DRUG synergism</searchLink><br /><searchLink fieldCode="DE" term="%22PANCREATIC+cancer%22">PANCREATIC cancer</searchLink><br /><searchLink fieldCode="DE" term="%22KINASE+inhibitors%22">KINASE inhibitors</searchLink><br /><searchLink fieldCode="DE" term="%22DNA+damage%22">DNA damage</searchLink><br /><searchLink fieldCode="DE" term="%22CHECKPOINT+kinase+1%22">CHECKPOINT kinase 1</searchLink><br /><searchLink fieldCode="DE" term="%22DNA+repair%22">DNA repair</searchLink>
– Name: Abstract
  Label: Abstract
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  Data: The DNA-damaging agent Gemcitabine (GEM) is a first-line treatment for pancreatic cancer, but chemoresistance is frequently observed. Several clinical trials investigate the efficacy of GEM in combination with targeted drugs, including kinase inhibitors, but the experimental evidence for such rationale is often unclear. Here, we phenotypically screened 13 human pancreatic adenocarcinoma (PDAC) cell lines against GEM in combination with 146 clinical inhibitors and observed strong synergy for the ATR kinase inhibitor Elimusertib in most cell lines. Dose-dependent phosphoproteome profiling of four ATR inhibitors following DNA damage induction by GEM revealed a strong block of the DNA damage response pathway, including phosphorylated pS468 of CHEK1, as the underlying mechanism of drug synergy. The current work provides a strong rationale for why the combination of GEM and ATR inhibition may be useful for the treatment of PDAC patients and constitutes a rich phenotypic and molecular resource for further investigating effective drug combinations. Synopsis: Phosphoproteomics unveils the mode of action of clinical ATR inhibitors and explains their synergy with Gemcitabine in pancreatic cancer cells. Viability screening of 146 targeted drugs identified ATR kinase inhibitor Elimusertib to broadly synergize with Gemcitabine across 13 PDAC cell lines. Phosphoproteomics revealed strong DNA damage induction by Gemcitabine and simultaneous blockage of DNA repair pathways by ATR inhibition as mechanism of drug synergy. The mechanistic insights presented herein provide a molecular rationale for the clinical use of combined Gemcitabine and ATR inhibitors in PDAC patients. Phosphoproteomics unveils the mode of action of clinical ATR inhibitors and explains their synergy with Gemcitabine in pancreatic cancer cells. [ABSTRACT FROM AUTHOR]
– Name: Abstract
  Label:
  Group: Ab
  Data: <i>Copyright of Molecular Systems Biology is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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        Value: 10.1038/s44320-025-00085-6
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        Text: English
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              Text: Mar2025
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