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CHK1 inhibition is synthetically lethal with loss of B-family DNA polymerase function in human lung and colorectal cancer cells

Rogers, Rebecca F, Walton, Mike I., Cherry, Daniel L, Collins, Ian, Clarke, Paul A, Garrett, Michelle D., Workman, Paul (2020) CHK1 inhibition is synthetically lethal with loss of B-family DNA polymerase function in human lung and colorectal cancer cells. Cancer Research, . ISSN 0008-5472. (doi:10.1158/0008-5472.CAN-19-1372) (KAR id:80536)

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Checkpoint kinase 1 (CHK1) is a key mediator of the DNA damage response that regulates cell cycle progression, DNA damage repair and DNA replication. Smallmolecule CHK1 inhibitors sensitise 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 largescale siRNA screen to identify novel mediators of CHK1 inhibitor sensitivity and uncover potential combination therapies and biomarkers for patient selection. We identified members of the B-family of DNA polymerases (POLA1, POLE and POLE2) whose silencing sensitised 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, pharmacological 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.

Item Type: Article
DOI/Identification number: 10.1158/0008-5472.CAN-19-1372
Subjects: Q Science
R Medicine
Divisions: Divisions > Division of Natural Sciences > School of Biosciences
Depositing User: Michelle Garrett
Date Deposited: 18 Mar 2020 10:04 UTC
Last Modified: 10 Mar 2021 00:00 UTC
Resource URI: (The current URI for this page, for reference purposes)
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