Journal article
Inhibition of the ATR-CHK1 pathway in Ewing sarcoma cells causes DNA damage and apoptosis via the CDK2-mediated degradation of RRM2
Molecular cancer research, Vol.18(1), pp.91-104
10/24/2019
DOI: 10.1158/1541-7786.MCR-19-0585
PMCID: PMC6942212
PMID: 31649026
Abstract
Inhibition of ribonucleotide reductase (RNR), the rate-limiting enzyme in the synthesis of deoxyribonucleotides, causes DNA replication stress and activates the ATR-CHK1 pathway. Notably, a number of different cancers, including Ewing sarcoma tumors, are sensitive to the combination of RNR and ATR-CHK1 inhibitors. However, multiple, overlapping mechanisms are reported to underlie the toxicity of ATR-CHK1 inhibitors, both as single-agents and in combination with RNR inhibitors, toward cancer cells. Here, we identified a feedback loop in Ewing sarcoma cells in which inhibition of the ATR-CHK1 pathway depletes RRM2, the small subunit of RNR, and exacerbates the DNA replication stress and DNA damage caused by RNR inhibitors. Mechanistically, we identified that the inhibition of ATR-CHK1 activates CDK2, which targets RRM2 for degradation via the proteasome. Similarly, activation of CDK2 by inhibition or knockdown of the WEE1 kinase also depletes RRM2 and causes DNA damage and apoptosis. Moreover, we show that the concurrent inhibition of ATR and WEE1 has a synergistic effect in Ewing sarcoma cells. Overall, our results provide novel insight into the response to DNA replication stress, as well as a rationale for targeting the ATR, CHK1, and WEE1 pathways, in Ewing sarcoma tumors.
Details
- Title: Subtitle
- Inhibition of the ATR-CHK1 pathway in Ewing sarcoma cells causes DNA damage and apoptosis via the CDK2-mediated degradation of RRM2
- Creators
- Stacia L. Koppenhafer - University of IowaKelli L. Goss - University of IowaWilliam W. Terry - University of IowaDavid J. Gordon - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Molecular cancer research, Vol.18(1), pp.91-104
- DOI
- 10.1158/1541-7786.MCR-19-0585
- PMID
- 31649026
- PMCID
- PMC6942212
- ISSN
- 1541-7786
- eISSN
- 1557-3125
- Grant note
- DOI: 10.13039/100000002, name: NIH, award: R37-CA217910; DOI: 10.13039/100000002, name: NIH NCI, award: P30CA086862
- Language
- English
- Date published
- 10/24/2019
- Academic Unit
- Stead Family Department of Pediatrics; Hematology/Oncology
- Record Identifier
- 9984353935902771
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