CHK2 Inhibition Provides a Strategy to Suppress Hematologic Toxicity from PARP Inhibitors.
Zhen XuCassandra J VandenbergElizabeth LieschkeLadina Di RagoClare L ScottIan J MajewskiPublished in: Molecular cancer research : MCR (2021)
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-blunted PARPi response in lymphoid and myeloid cell lines, and in primary murine pre-B/pro-B cells. Using a Cas9 base editor, we found that blocking CHK2-mediated phosphorylation of p53 also impaired olaparib response. Our results identify the p53 pathway as a major determinant of the acute response to PARPi in normal blood cells and demonstrate that targeting CHK2 can short circuit this response. Cotreatment with a CHK2 inhibitor did not antagonize olaparib response in ovarian cancer cell lines. Selective inhibition of CHK2 may spare blood cells from the toxic influence of PARPi and broaden the utility of these drugs. IMPLICATIONS: We reveal that genetic or pharmacologic inhibition of CHK2 may offer a way to alleviate the toxic influence of PARPi in the hematologic system.
Keyphrases
- dna damage response
- dna repair
- dna damage
- crispr cas
- genome wide
- protein kinase
- oxidative stress
- cancer therapy
- high throughput
- transcription factor
- intensive care unit
- diffuse large b cell lymphoma
- gene expression
- immune response
- metabolic syndrome
- cell cycle
- induced apoptosis
- replacement therapy
- liver failure
- tyrosine kinase
- acute myeloid leukemia
- smoking cessation
- combination therapy
- diabetic rats
- aortic dissection