Synthetic lethality of Chk1 inhibition combined with p53 and/or p21 loss during a DNA damage response in normal and tumor cells
Open accessAbstract
Cell cycle checkpoints ensure genome integrity and are frequently compromised in human cancers. A therapeutic strategy being explored takes advantage of checkpoint defects in p53-deficient tumors in order to sensitize them to DNA-damaging agents by eliminating Chk1-mediated checkpoint responses. Using mouse models, we demonstrated that p21 is a key determinant of how cells respond to the combination of DNA damage and Chk1 inhibition (combination therapy) in normal cells as well as in tumors. Loss of p21 sensitized normal cells to the combination therapy much more than did p53 loss and the enhanced lethality was partially blocked by CDK inhibition. In addition, basal pools of p21 (p53 independent) provided p53 null cells with protection from the combination therapy. Our results uncover a novel p53-independent function for p21 in protecting cells from the lethal effects of DNA damage followed by Chk1 inhibition. As p21 levels are low in a significant fraction of colorectal tumors, they are predicted to be particularly sensitive to the combination therapy. Results reported in this study support this prediction.
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Endogenous p21 expression in the S phase protects cancer cells from excessive DNA damage in the S phase and from cell killing by Wee1 and Chk1 kinase inhibitors.
“Intriguingly, endogenous p21 expression in the S phase was recently reported to protect cancer cells from excessive DNA damage in the S phase, and cell killing by Wee1 (MK1775) and Chk1 (AZD6772) kinase inhibitors [84,85].”
From CDK-Independent and PCNA-Dependent Functions of p21 in DNA Replication (2020) · cites this paper as [85]
Targeting p21 may have positive results in the clinic.
“the targeting of p21 may have positive results in the clinic [84,85]”
From CDK-Independent and PCNA-Dependent Functions of p21 in DNA Replication (2020) · cites this paper as [85]
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- [19]Sedelnikova OA Pilch DR Redon C Bonner WM Histone H2AX in DNA damage and repair Cancer Biol Ther 2003 2 3 233 5 Epub 2003/07/25 12878854
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- Authors
- Origanti, S., Cai, S.-R., Munir, A. Z., White, L. S., & Piwnica-Worms, H.
- Affiliations
- Washington University in St. Louis (US)
- Corresponding author
- Piwnica-Worms, H
- Venue
- Oncogene
- Published
- 2012-03-19
- Volume
- 32
- Issue
- 5
- Pages
- 577-588
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- PMC
- PMC3381958
- OpenAlex
- W2052287702
- Cited by
- 74
- References
- 41
- Citations by year
- 2025: 3 · 2024: 4 · 2023: 7 · 2022: 3 · 2021: 4 · 2020: 4 · 2019: 6 · 2018: 7 · 2017: 4 · 2016: 7 · 2015: 5 · 2014: 8 · 2013: 11 · 2012: 1
- FWCI
- 3.93
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Oncogene (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- e-Publications@Marquette (Marquette University) (submittedVersion)
- Funders
- American Cancer Society
- National Institutes of Health
- National Cancer Institute (P50CA094056)
- National Institute of General Medical Sciences (GM047017, R01GM047017)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Keywords
- CHK1 inhibition, p53, p21, DNA damage response, synthetic lethality, cell cycle checkpoints, CDK inhibition, colorectal cancer, combination therapy, tumor cell sensitivity
- MeSH terms
- Checkpoint Kinase 1, Irinotecan, Animals, Antineoplastic Agents, Phytogenic, Camptothecin, DNA Damage, Protein Kinases, Tumor Suppressor Protein p53, Apoptosis, Mice, Knockout, Cell Line, Tumor, Protein Kinase Inhibitors, Cyclin-Dependent Kinase Inhibitor p21, Mice, Cell Cycle Checkpoints
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