Journal article

CHK2 Inhibition Provides a Strategy to Suppress Hematologic Toxicity from PARP Inhibitors

Zhen Xu, Cassandra J Vandenberg, Elizabeth Lieschke, Ladina Di Rago, Clare L Scott, Ian J Majewski



Patients with cancer treated with PARP inhibitors (PARPi) experience various side effects, with hematologic toxicity being most common. Short-term treatment of mice with olaparib resulted in depletion of reticulocytes, B-cell progenitors, and immature thymocytes, whereas longer treatment induced broader myelosuppression. We performed a CRISPR/Cas9 screen that targeted DNA repair genes in Eμ-Myc pre-B lymphoma cell lines as a way to identify strategies to suppress hematologic toxicity from PARPi. The screen revealed that single-guide RNAs targeting the serine/threonine kinase checkpoint kinase 2 (CHK2) were enriched following olaparib treatment. Genetic or pharmacologic inhibition of CHK2-blu..

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Awarded by National Health and Medical Research Council of Australia

Awarded by Victorian Cancer Agency

Funding Acknowledgements

The authors wish to acknowledge Andreas Strasser and Raelene Endersby for thoughtful feedback on the manuscript. We wish to thank Rachel Hancock, Stephanie Bound, and Laura Dunleavy for assistance with animal husbandry and drug treatment experiments, Chris Riffkin and Ksenija Nesic provided guidance with ovarian cancer cell lines, and Martin Pal and Marco Herold for advice with CRISPR base editing. This research has been supported by project funding from the National Health and Medical Research Council of Australia (project grant no. 1145912, to I.J. Majewski), the Cancer Council of Victoria (to I.J. Majewski) and the Stafford Fox Medical Research Foundation (to C.L. Scott and C.J. Vandenberg). Fellowship support was provided from the Felton Bequest (to I.J. Majewski) and the Victorian Cancer Agency (Clinical Fellowship to C.L. Scott; CRF16014 and MCRF15018 to I.J. Majewski), and scholarship support from the Leukaemia Foundation and the Haematology Society of Australia and New Zealand (to E. Lieschke). Research was also made possible through the Australian Cancer Research Foundation, Victorian State Government Operational Infrastructure Support and Australian Government NHMRC IRIISS. The funders had no influence over the final content of the article.