RNAi screen of the protein kinome identifies checkpoint kinase 1 (CHK1) as a therapeutic target in neuroblastoma
Open accessAbstract
Neuroblastoma is a childhood cancer that is often fatal despite intense multimodality therapy. In an effort to identify therapeutic targets for this disease, we performed a comprehensive loss-of-function screen of the protein kinome. Thirty kinases showed significant cellular cytotoxicity when depleted, with loss of the cell cycle checkpoint kinase 1 (CHK1/CHEK1) being the most potent. CHK1 mRNA expression was higher in MYC–Neuroblastoma-related (MYCN)– amplified ( P < 0.0001) and high-risk ( P = 0.03) tumors. Western blotting revealed that CHK1 was constitutively phosphorylated at the ataxia telangiectasia response kinase target site Ser345 and the autophosphorylation site Ser296 in neuroblastoma cell lines. This pattern was also seen in six of eight high-risk primary tumors but not in control nonneuroblastoma cell lines or in seven of eight low-risk primary tumors. Neuroblastoma cells were sensitive to the two CHK1 inhibitors SB21807 and TCS2312, with median IC 50 values of 564 nM and 548 nM, respectively. In contrast, the control lines had high micromolar IC 50 values, indicating a strong correlation between CHK1 phosphorylation and CHK1 inhibitor sensitivity ( P = 0.0004). Furthermore, cell cycle analysis revealed that CHK1 inhibition in neuroblastoma cells caused apoptosis during S-phase, consistent with its role in replication fork progression. CHK1 inhibitor sensitivity correlated with total MYC(N) protein levels, and inducing MYCN in retinal pigmented epithelial cells resulted in CHK1 phosphorylation, which caused growth inhibition when inhibited. These data show the power of a functional RNAi screen to identify tractable therapeutical targets in neuroblastoma and support CHK1 inhibition strategies in this disease.
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CHK1 inhibitors and glutaminase inhibitors are considered potential candidates for treating Myc-overexpressing cancers.
“Similarly, checkpoint kinase 1 (CHK1) inhibitors625–627 and glutaminase (GLS) inhibitors628–634 are also considered potential candidates for treating Myc-overexpressing cancers.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [625]
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- Authors
- Cole, K. A., Huggins, J., Laquaglia, M., Hulderman, C. E., Russell, M. R., Bosse, K., Diskin, S. J., Attiyeh, E. F., Sennett, R., Norris, G., Laudenslager, M., Wood, A. C., Mayes, P. A., Jagannathan, J., Winter, C., Mosse, Y. P., & Maris, J. M.
- Affiliations
- Children's Hospital of Philadelphia (US)
- Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA 19104-4318;
- Corresponding author
- Maris, John M.
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2011-02-02
- Volume
- 108
- Issue
- 8
- Pages
- 3336-3341
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3044382
- OpenAlex
- W2030646897
- Cited by
- 249
- References
- 34
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 8 · 2023: 12 · 2022: 10 · 2021: 23 · 2020: 24 · 2019: 12 · 2018: 15 · 2017: 19 · 2016: 22 · 2015: 21 · 2014: 17 · 2013: 20 · 2012: 27
- FWCI
- 15.41
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Cancer Research Institute
- Alex's Lemonade Stand Foundation for Childhood Cancer
- University of Pennsylvania
- Children’s Oncology Group
- National Institutes of Health (5k08ca136979-05, CA98543)
- National Cancer Institute (U10-CA98543, K08-CA136979, K08 CA13697901, R01CA087847, R01-CA87847, U10CA098543)
- Abramson Family Cancer Research Institute
- Topics
- Health Sciences › Medicine › Neurology › Neuroblastoma Research and Treatments
- Health Sciences › Medicine › Neurology › Neurofibromatosis and Schwannoma Cases
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Keywords
- neuroblastoma, Chk1, RNAi screen, drug target identification, MYCN amplification, Chk1 phosphorylation, CHK1 inhibitor, apoptosis, S phase, replication fork progression, retinal pigment epithelial cells, high-risk neuroblastoma
- MeSH terms
- N-Myc Proto-Oncogene Protein, Checkpoint Kinase 1, Drug Evaluation, Preclinical, Humans, Neuroblastoma, Nuclear Proteins, Phosphorylation, Protein Kinases, RNA, Messenger, Oncogene Proteins, S Phase, Drug Delivery Systems, Apoptosis, RNA, Small Interfering, Protein Kinase Inhibitors
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