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dc.contributor.authorRogers, RF
dc.contributor.authorWalton, MI
dc.contributor.authorCherry, DL
dc.contributor.authorCollins, I
dc.contributor.authorClarke, PA
dc.contributor.authorGarrett, MD
dc.contributor.authorWorkman, P
dc.date.accessioned2020-04-02T11:31:31Z
dc.date.issued2020-04
dc.identifier.citationCancer research, 2020, 80 (8), pp. 1735 - 1747
dc.identifier.issn0008-5472
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3573
dc.identifier.eissn1538-7445
dc.identifier.doi10.1158/0008-5472.can-19-1372
dc.description.abstractCheckpoint kinase 1 (CHK1) is a key mediator of the DNA damage response that regulates cell-cycle progression, DNA damage repair, and DNA replication. Small-molecule CHK1 inhibitors sensitize cancer cells to genotoxic agents and have shown single-agent preclinical activity in cancers with high levels of replication stress. However, the underlying genetic determinants of CHK1 inhibitor sensitivity remain unclear. We used the developmental clinical drug SRA737 in an unbiased large-scale siRNA screen to identify novel mediators of CHK1 inhibitor sensitivity and uncover potential combination therapies and biomarkers for patient selection. We identified subunits of the B-family of DNA polymerases ( POLA1, POLE , and POLE2 ) whose silencing sensitized the human A549 non-small cell lung cancer (NSCLC) and SW620 colorectal cancer cell lines to SRA737. B-family polymerases were validated using multiple siRNAs in a panel of NSCLC and colorectal cancer cell lines. Replication stress, DNA damage, and apoptosis were increased in human cancer cells following depletion of the B-family DNA polymerases combined with SRA737 treatment. Moreover, pharmacologic blockade of B-family DNA polymerases using aphidicolin or CD437 combined with CHK1 inhibitors led to synergistic inhibition of cancer cell proliferation. Furthermore, low levels of POLA1, POLE, and POLE2 protein expression in NSCLC and colorectal cancer cells correlated with single-agent CHK1 inhibitor sensitivity and may constitute biomarkers of this phenotype. These findings provide a potential basis for combining CHK1 and B-family polymerase inhibitors in cancer therapy. SIGNIFICANCE: These findings demonstrate how the therapeutic benefit of CHK1 inhibitors may potentially be enhanced and could have implications for patient selection and future development of new combination therapies.
dc.formatPrint-Electronic
dc.format.extent1735 - 1747
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.subjectCell Line, Tumor
dc.subjectHumans
dc.subjectColorectal Neoplasms
dc.subjectLung Neoplasms
dc.subjectDNA Damage
dc.subjectRetinoids
dc.subjectAphidicolin
dc.subjectDNA Polymerase beta
dc.subjectDNA Polymerase I
dc.subjectDNA Polymerase II
dc.subjectNeoplasm Proteins
dc.subjectRNA, Small Interfering
dc.subjectDrugs, Investigational
dc.subjectEnzyme Inhibitors
dc.subjectCell Cycle
dc.subjectApoptosis
dc.subjectCell Proliferation
dc.subjectGene Knockdown Techniques
dc.subjectHeterocyclic Compounds, 4 or More Rings
dc.subjectCheckpoint Kinase 1
dc.subjectPoly-ADP-Ribose Binding Proteins
dc.titleCHK1 Inhibition Is Synthetically Lethal with Loss of B-Family DNA Polymerase Function in Human Lung and Colorectal Cancer Cells.
dc.typeJournal Article
dcterms.dateAccepted2020-02-20
rioxxterms.versionofrecord10.1158/0008-5472.can-19-1372
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2020-04
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfCancer research
pubs.issue8
pubs.notesNot known
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Medicinal Chemistry 2
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Signal Transduction & Molecular Pharmacology
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Medicinal Chemistry 2
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Signal Transduction & Molecular Pharmacology
pubs.publication-statusPublished
pubs.volume80
pubs.embargo.termsNot known
icr.researchteamMedicinal Chemistry 2en_US
icr.researchteamSignal Transduction & Molecular Pharmacologyen_US
dc.contributor.icrauthorClarke, Paulen
dc.contributor.icrauthorWorkman, Paulen
dc.contributor.icrauthorCollins, Ianen


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