The DOI matches its Crossref record; 27 of the 27 references it cites were found in a registry or an index.
Combined CDKN1A/TP53 Mutation in Bladder Cancer Is a Therapeutic Target
Open accessAbstract
Invasive bladder cancer has high morbidity and nearly uniform mortality when metastatic, with no therapeutic improvement in many years. Although chemotherapy combined with Chk1 inhibition has been investigated in several cancer types in which TP53 mutation is seen, this combination treatment approach has not been studied in bladder cancer. Recently, cancer genome sequencing efforts have identified CDKN1A (p21) mutations at 14% frequency in invasive bladder cancer, co-occurring half the time with TP53 mutations. We hypothesized that combined CDKN1A–TP53 loss would make bladder cancer sensitive to combined treatment with gemcitabine and Chk1 inhibitor. Here, we show that TP53–CDKN1A double-mutant bladder cancer cell lines, 647V and RT-112, have a remarkable increase in p-Chk1 levels and G2–M arrest in response to gemcitabine treatment, with a heightened sensitivity to combination treatment with gemcitabine and either Chk1 inhibitor PF477736 or AZD7762, in comparison with other bladder cancer cell lines (either TP53 or p21 deficient). In addition, CDKN1A restoration in p21-deficient bladder cancer cells significantly reduced their sensitivity to combined treatment by protecting them from DNA damage and apoptosis. Furthermore, xenograft studies using RT-112 showed a significant synergistic effect of combined gemcitabine–PF477736 treatment on tumor growth. Our findings suggest that TP53/CDKN1A double-mutant bladder cancer cells have a unique dependence on Chk1 activity for the G2–M cell-cycle checkpoint in response to chemotherapy-induced DNA damage. This combination or others involving genotoxic agents and Chk kinase inhibitors is a promising therapeutic approach for bladder cancer with these mutations. Mol Cancer Ther; 14(1); 174–82. ©2014 AACR.
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“However, mutations in p21 are rarely observed in human cancers, except for bladder cancer [30], possibly due to its anti-apoptotic function [31].”
From The role of cellular senescence and SASP in tumour microenvironment (2023) · cites this paper as [30]
In the citing paper
“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 [84]
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“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 [84]
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Cites
Comprehensive molecular characterization of urothelial bladder carcinoma
Perou, C. M. (2014) · Carolina Digital Repository (University of North Carolina at Chapel Hill) · doi:10.17615/za09-dk57 · Cited by 2,922
Cell-cycle checkpoints and cancer
Kastan, M. B., & Bartek, J. (2004) · Nature · doi:10.1038/nature03097 · Cited by 2,836
Comprehensive molecular characterization of urothelial bladder carcinoma
Weinstein, J. N., Akbani, R., Broom, B. M., Wang, W., Verhaak, R. G. W., Liu, W., Ju, Z., Motter, T., Peng, B., Ryan, M., et al. (2014) · Nature · doi:10.1038/nature12965 · Cited by 2,746
Self-citationCell Cycle Checkpoints: Preventing an Identity Crisis
Elledge, S. J. (1996) · Science · doi:10.1126/science.274.5293.1664 · Cited by 2,050
Cell cycle checkpoint signaling through the ATM and ATR kinases
Abraham, R. T. (2001) · Genes & Development · doi:10.1101/gad.914401 · Cited by 1,966
The ATM–Chk2 and ATR–Chk1 Pathways in DNA Damage Signaling and Cancer
Smith, J., Tho, L. M., Xu, N., & Gillespie, D. A. (2010) · Advances in cancer research · doi:10.1016/b978-0-12-380888-2.00003-0 · Cited by 1,331
Graves, P. R., Yu, L., Schwarz, J. K., Gales, J., Sausville, E. A., O'Connor, P. M., & Piwnica-Worms, H. M. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.8.5600 · Cited by 540
Zhao, H., Watkins, J. L., & Piwnica-Worms, H. M. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.182557299 · Cited by 472
UCN-01: a potent abrogator of G2 checkpoint function in cancer cells with disrupted p53
Wang, Q., Fan, S., Eastman, A., Worland, P. J., Sausville, E. A., & O'Connor, P. M. (1996) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/88.14.956 · Cited by 453
A p53-Dependent Checkpoint Pathway Prevents Rereplication
Vaziri, C., Saxena, S., Jeon, Y., Lee, C., Murata, K., Machida, Y., Wagle, N., Hwang, D. S., & Dutta, A. (2003) · Molecular Cell · doi:10.1016/s1097-2765(03)00099-6 · Cited by 393
Cited by
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Shamloo, B., & Usluer, S. (2019) · Cancers · doi:10.3390/cancers11081178 · Cited by 336
The role of cellular senescence and SASP in tumour microenvironment
Takasugi, M., Yoshida, Y., Hara, E., & Ohtani, N. (2023) · The FEBS Journal · doi:10.1111/febs.16381 · Cited by 144
CDK-Independent and PCNA-Dependent Functions of p21 in DNA Replication
Mansilla, S. F., De La Vega, M. B., Calzetta, N. L., Siri, S. O., & Gottifredi, V. (2020) · Genes · doi:10.3390/genes11060593 · Cited by 114
p21 limits S phase DNA damage caused by the Wee1 inhibitor MK1775
Hauge, S., Macurek, L., & Syljuåsen, R. G. (2019) · Cell Cycle · doi:10.1080/15384101.2019.1593649 · Cited by 30
Metadata
- Authors
- Liu, Y., & Kwiatkowski, D. J.
- Affiliations
- Brigham and Women's Hospital (US)
- Corresponding author
- Kwiatkowski, David J.
- Venue
- Molecular Cancer Therapeutics
- Published
- 2015-01-01
- Volume
- 14
- Issue
- 1
- Pages
- 174-182
- ISSN
- 1535-7163 (ISSN-L)
- 1538-8514
- PMC
- PMC4297264
- OpenAlex
- W2147531617
- Cited by
- 35
- References
- 27
- Citations by year
- 2025: 3 · 2023: 2 · 2022: 8 · 2021: 2 · 2020: 3 · 2019: 5 · 2018: 1 · 2017: 5 · 2016: 2 · 2015: 4
- FWCI
- 3.64
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular Cancer Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (P01CA120964)
- Topics
- Health Sciences › Medicine › Surgery › Bladder and Urothelial Cancer Treatments
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Keywords
- invasive bladder cancer, TP53 mutation, p21, CHK1 inhibition, gemcitabine, AZD7762, G2/M checkpoint, DNA damage response, apoptosis, combination chemotherapy, therapeutic target, xenograft tumor growth
- MeSH terms
- Checkpoint Kinase 1, Gemcitabine, Animals, Antineoplastic Combined Chemotherapy Protocols, Benzodiazepinones, Urinary Bladder Neoplasms, Cell Cycle, Deoxycytidine, Drug Synergism, Humans, Mutation, Protein Kinases, Pyrazoles, Thiophenes, Urea, Tumor Suppressor Protein p53, Xenograft Model Antitumor Assays, Cell Line, Tumor, Cyclin-Dependent Kinase Inhibitor p21, Mice
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- Liu, Y., & Kwiatkowski, D. J. (2015). Combined CDKN1A/TP53 Mutation in Bladder Cancer Is a Therapeutic Target. Molecular Cancer Therapeutics. https://doi.org/10.1158/1535-7163.mct-14-0622-t
