ArticleBritish journal of cancer2018
pRAD50: a novel and clinically applicable pharmacodynamic biomarker of both ATM and ATR inhibition identified using mass spectrometry and immunohistochemistry.
Article in British journal of cancer, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 35 citations in OpenAlex.
- The DNA-PK inhibitor AZD7648 alone or combined with pegylated liposomal doxorubicin in patients with advanced cancer: results of a first-in-human Phase I/IIa study.British journal of cancer · 2025Trial
- Safety and efficacy of ceralasertib, an ATR kinase inhibitor, combined with olaparib: dose escalation in advanced solid tumours and dose expansion in advanced breast cancer.British journal of cancer · 2026Article
- Phase 1 study of ceralasertib, an ATR kinase inhibitor, in combination with durvalumab in patients with recurrent or metastatic NSCLC or HNSCC.British journal of cancer · 2026Article
- Medicinal chemistry breakthroughs on ATM, ATR, and DNA-PK inhibitors as prospective cancer therapeutics.Journal of enzyme inhibition and medicinal chemistry · 2025Review
- Antioxidants and azd0156 Rescue Inflammatory Response in Autophagy-Impaired Macrophages.International journal of molecular sciences · 2023Article
- Review
- Relevance of ATM Status in Driving Sensitivity to DNA Damage Response Inhibitors in Patient-Derived Xenograft Models.Cancers · 2023Article
- Epitope Lability of Phosphorylated Biomarkers of the DNA Damage Response Pathway Results in Increased Vulnerability to Effects of Delayed or Incomplete Formalin Fixation.The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society · 2023Article
- ATM kinase inhibitor AZD0156 in combination with irinotecan and 5-fluorouracil in preclinical models of colorectal cancer.BMC cancer · 2022Article
- Perspective on the Use of DNA Repair Inhibitors as a Tool for Imaging and Radionuclide Therapy of Glioblastoma.Cancers · 2022Review
- ATR Inhibitor AZD6738 (Ceralasertib) Exerts Antitumor Activity as a Monotherapy and in Combination with Chemotherapy and the PARP Inhibitor Olaparib.Cancer research · 2022Article
- Retrospective analysis of Schlafen11 (SLFN11) to predict the outcomes to therapies affecting the DNA damage response.British journal of cancer · 2021Article
- Ceralasertib (AZD6738), an Oral ATR Kinase Inhibitor, in Combination with Carboplatin in Patients with Advanced Solid Tumors: A Phase I Study.Clinical cancer research : an official journal of the American Association for Cancer Research · 2021Article
- DNA damage repair in glioblastoma: current perspectives on its role in tumour progression, treatment resistance and PIKKing potential therapeutic targets.Cellular oncology (Dordrecht, Netherlands) · 2021Review
- Phase I Study of Ceralasertib (AZD6738), a Novel DNA Damage Repair Agent, in Combination with Weekly Paclitaxel in Refractory Cancer.Clinical cancer research : an official journal of the American Association for Cancer Research · 2021Article
- Quantitative Image Analysis for Tissue Biomarker Use: A White Paper From the Digital Pathology Association.Applied immunohistochemistry & molecular morphology : AIMM · 2021Article
- Targeted Mass Spectrometry Enables Quantification of Novel Pharmacodynamic Biomarkers of ATM Kinase Inhibition.Cancers · 2021Article
- Targeted mass spectrometry-based assays enable multiplex quantification of receptor tyrosine kinase, MAP Kinase, and AKT signaling.Cell reports methods · 2021Article
- The next horizon in precision oncology: Proteogenomics to inform cancer diagnosis and treatment.Cell · 2021Review
- SLFN11 informs on standard of care and novel treatments in a wide range of cancer models.British journal of cancer · 2021Article
Corrections and comments
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Authors and funding
20 authors at 2 institutions in 2 countries.
Funding
Abstract
backgroundAZD0156 and AZD6738 are potent and selective inhibitors of ataxia-telangiectasia-kinase (ATM) and ataxia-telangiectasia-mutated and Rad3-related (ATR), respectively, important sensors/signallers of DNA damage.
methodsWe used multiplexed targeted-mass-spectrometry to select pRAD50(Ser635) as a pharmacodynamic biomarker for AZD0156-mediated ATM inhibition from a panel of 45 peptides, then developed and tested a clinically applicable immunohistochemistry assay for pRAD50(Ser635) detection in FFPE tissue.
resultsWe found moderate pRAD50 baseline levels across cancer indications. pRAD50 was detectable in 100% gastric cancers (n = 23), 99% colorectal cancers (n = 102), 95% triple-negative-breast cancers (TNBC) (n = 40) and 87.5% glioblastoma-multiformes (n = 16). We demonstrated AZD0156 target inhibition in TNBC patient-derived xenograft models; where AZD0156 monotherapy or post olaparib treatment, resulted in a 34-72% reduction in pRAD50. Similar inhibition of pRAD50 (68%) was observed following ATM inhibitor treatment post irinotecan in a colorectal cancer xenograft model. ATR inhibition, using AZD6738, increased pRAD50 in the ATM-proficient models whilst in ATM-deficient models the opposite was observed, suggesting pRAD50 pharmacodynamics post ATR inhibition may be ATM-dependent and could be useful to determine ATM functionality in patients treated with ATR inhibitors.
conclusionTogether these data support clinical utilisation of pRAD50 as a biomarker of AZD0156 and AZD6738 pharmacology to elucidate clinical pharmacokinetic/pharmacodynamic relationships, thereby informing recommended Phase 2 dose/schedule.
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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.