Complete loss of ATM function augments replication catastrophe induced by ATR inhibition and gemcitabine in pancreatic cancer models

Background Personalised medicine strategies may improve outcomes in pancreatic ductal adenocarcinoma (PDAC), but validation of predictive biomarkers is required. Having developed a clinical trial to assess the ATR inhibitor, AZD6738, in combination with gemcitabine (ATRi/gem), we investigated ATM lo...

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Bibliographic Details
Published in:British journal of cancer Vol. 123; no. 9; pp. 1424 - 1436
Main Authors: Dunlop, Charles R., Wallez, Yann, Johnson, Timothy Isaac, Bernaldo de Quirós Fernández, Sandra, Durant, Stephen T., Cadogan, Elaine B., Lau, Alan, Richards, Frances M., Jodrell, Duncan I.
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 27.10.2020
Nature Publishing Group
Subjects:
631/154/53/2423
631/67/1059/602
631/67/1059/99
631/67/1504/1713
631/80/86/2371
Adenocarcinoma
Animals
Antineoplastic Combined Chemotherapy Protocols - therapeutic use
Ataxia Telangiectasia Mutated Proteins - antagonists & inhibitors
Ataxia Telangiectasia Mutated Proteins - genetics
Ataxia Telangiectasia Mutated Proteins - physiology
Biomarkers
Biomedical and Life Sciences
Biomedicine
Cancer Research
Carcinoma, Pancreatic Ductal - drug therapy
Carcinoma, Pancreatic Ductal - pathology
Cell death
Cell Line, Tumor
Cell Proliferation - drug effects
Clinical trials
CRISPR
Deoxycytidine - analogs & derivatives
Deoxycytidine - pharmacology
Deoxycytidine - therapeutic use
DNA-dependent protein kinase
Drug Resistance
Drug Synergism
Epidemiology
Female
Flow cytometry
Gemcitabine
Gene Knockout Techniques
Humans
Immunoblotting
Immunofluorescence
Indoles
Mice
Mice, 129 Strain
Mice, Inbred C57BL
Molecular Medicine
Morpholines
Oncology
Pancreatic cancer
Pancreatic Neoplasms - drug therapy
Pancreatic Neoplasms - pathology
Precision medicine
Pyridines - administration & dosage
Pyridines - pharmacology
Pyrimidines - administration & dosage
Pyrimidines - pharmacology
Quinolines - administration & dosage
Quinolines - pharmacology
Replication
RNA, Small Interfering - pharmacology
siRNA
Sulfonamides
Sulfoxides - administration & dosage
Sulfoxides - pharmacology
Tumors
Xenograft Model Antitumor Assays
Xenografts
ISSN:0007-0920, 1532-1827, 1532-1827
Online Access:Get full text
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Summary:Background Personalised medicine strategies may improve outcomes in pancreatic ductal adenocarcinoma (PDAC), but validation of predictive biomarkers is required. Having developed a clinical trial to assess the ATR inhibitor, AZD6738, in combination with gemcitabine (ATRi/gem), we investigated ATM loss as a predictive biomarker of response to ATRi/gem in PDAC. Methods Through kinase inhibition, siRNA depletion and CRISPR knockout of ATM, we assessed how ATM targeting affected the sensitivity of PDAC cells to ATRi/gem. Using flow cytometry, immunofluorescence and immunoblotting, we investigated how ATRi/gem synergise in ATM-proficient and ATM-deficient cells, before assessing the impact of ATM loss on ATRi/gem sensitivity in vivo. Results Complete loss of ATM function (through pharmacological inhibition or CRISPR knockout), but not siRNA depletion, sensitised to ATRi/gem. In ATM-deficient cells, ATRi/gem-induced replication catastrophe was augmented, while phospho-Chk2-T68 and phospho-KAP1-S824 persisted via DNA-PK activity. ATRi/gem caused growth delay in ATM-WT xenografts in NSG mice and induced regression in ATM-KO xenografts. Conclusions ATM loss augments replication catastrophe-mediated cell death induced by ATRi/gem and may predict clinical responsiveness to this combination. ATM status should be carefully assessed in tumours from patients with PDAC, since distinction between ATM-low and ATM-null could be critical in maximising the success of clinical trials using ATM expression as a predictive biomarker.
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ISSN:0007-0920
1532-1827
1532-1827
DOI:10.1038/s41416-020-1016-2