ArticleGut2021
Synergistic targeting and resistance to PARP inhibition in DNA damage repair-deficient pancreatic cancer.
Article in Gut, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 51 papers, 1 of them a synthesis that pooled it.
What it found
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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.
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Who cites it
51 citing papers in PubMed, 1 synthesis or guideline pooled it, 75 citations in OpenAlex.
- DNA damage repair mutations in pancreatic cancer- prognostic or predictive?Frontiers in oncology · 2023Pooled it
- Exploring trop-2-directed ADCs monotherapy and combination therapy in pretreated mTNBC: a real-world study.Breast cancer research and treatment · 2026Article
- ATM Deficiency Induces TGFβ-Mediated Stromal Programming in Pancreatic Cancer.Cancer research · 2026Article
- PARG inhibition in ATM-deficient prostate cancer: from mechanistic discovery to therapeutic potential.Journal of translational medicine · 2026Article
- DKK3 Initially Preserves Acinar Integrity Through MEK-Fos Signaling, but Later Switches to an Oncogenic Role in Pancreatic Cancer.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- DNA damage response inhibitors in pancreatic cancer: progress and challenges.Frontiers in oncology · 2026Review
- Review
- Genomic and Immune Landscape of Pancreatic Ductal Adenocarcinoma Associated with Germline Pathogenic Variants in ATM.Clinical cancer research : an official journal of the American Association for Cancer Research · 2025Article
- Molecular Pathology of Pancreatic Ductal Adenocarcinoma.Cancers · 2025Review
- Endocrine cancer organoids in basic and translational medical research.Science China. Life sciences · 2025Review
- Homologous Repair-Deficient Pancreatic Cancer: Refined Targeting of DNA Damage Response is an Effective Therapeutic Strategy.United European gastroenterology journal · 2025Article
- Proteomics in pancreatic cancer.Biomarker research · 2025Review
- Reversing regulatory safeguards: Targeting the ATR pathway to overcome PARP inhibitor resistance.Molecular therapy. Oncology · 2025Review
- ATR inhibition potentiates FOLFIRINOX cytotoxic effect in models of pancreatic ductal adenocarcinoma by remodelling the tumour microenvironment.British journal of cancer · 2025Article
- Combination of S-1 and the oral ATR inhibitor ceralasertib is effective against pancreatic cancer cells.Cancer chemotherapy and pharmacology · 2024Article
- NLRP4 renders pancreatic cancer resistant to olaparib through promotion of the DNA damage response and ROS-induced autophagy.Cell death & disease · 2024Article
- Mutational signature-based identification of DNA repair deficient gastroesophageal adenocarcinomas for therapeutic targeting.NPJ precision oncology · 2024Article
- Small molecule agents for triple negative breast cancer: Current status and future prospects.Translational oncology · 2024Review
- Higher Expression of Ku80 and Ku70 Indicates Hotter Tumor Immune Microenvironment in Hepatocellular Carcinoma and Better CTL-Centered Immunotherapy.Journal of inflammation research · 2024Article
- Unravelling the molecular basis of PARP inhibitor resistance in prostate cancer with homologous recombination repair deficiency.International review of cell and molecular biology · 2024Review
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
31 authors at 11 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
objective
designCombinational synergy screening was performed to endeavour a genotype-tailored targeted therapy.
resultsSynergy was found on inhibition of PARP, ATR and DNA-PKcs (PAD) leading to synthetic lethality in ATM-deficient murine and human PDAC. Mechanistically, PAD-induced PARP trapping, replication fork stalling and mitosis defects leading to P53-mediated apoptosis. Most importantly, chemical inhibition of ATM sensitises human PDAC cells toward PAD with long-term tumour control in vivo. Finally, we anticipated and elucidated PARP inhibitor resistance within the ATM-null background via whole exome sequencing. Arising cells were aneuploid, underwent epithelial-mesenchymal-transition and acquired multidrug resistance (MDR) due to upregulation of drug transporters and a bypass within the DNA repair machinery. These functional observations were mirrored in copy number variations affecting a region on chromosome 5 comprising several of the upregulated MDR genes. Using these findings, we ultimately propose alternative strategies to overcome the resistance.
conclusionAnalysis of the molecular susceptibilities triggered by ATM deficiency in PDAC allow elaboration of an efficient mutation-specific combinational therapeutic approach that can be also implemented in a genotype-independent manner by ATM inhibition.
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What OpenQuestion holds
Registered trials
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.