ArticleMolecular cancer therapeutics2015
Combined CDKN1A/TP53 mutation in bladder cancer is a therapeutic target.
Article in Molecular cancer therapeutics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 36 citations in OpenAlex.
- Article
- Distinct adaptive strategies to cisplatin, vinblastine and gemcitabine in a panel of chemoresistant bladder cancer cell lines.Cancer drug resistance (Alhambra, Calif.) · 2025Article
- Cancer-keeper genes as therapeutic targets.iScience · 2023Article
- Article
- Inhibition of PP2A by LB100 sensitizes bladder cancer cells to chemotherapy by inducing p21 degradation.Cellular oncology (Dordrecht, Netherlands) · 2022Article
- Applications of Exosomes in Diagnosing Muscle Invasive Bladder Cancer.Pharmaceutics · 2022Review
- The origin of bladder cancer from mucosal field effects.iScience · 2022Article
- Copy number variation analysis of mCancer medicine · 2021Article
- Differential Effects of Clinically Relevant N- versus C-Terminal Truncating CDKN1A Mutations on Cisplatin Sensitivity in Bladder Cancer.Molecular cancer research : MCR · 2021Article
- Pure high-grade papillary urothelial bladder cancer: a luminal-like subgroup with potential for targeted therapy.Cellular oncology (Dordrecht, Netherlands) · 2020Article
- Review
- p21 in Cancer Research.Cancers · 2019Review
- p21 limits S phase DNA damage caused by the Wee1 inhibitor MK1775.Cell cycle (Georgetown, Tex.) · 2019Article
- Article
- Gemcitabine/Cisplatin Treatment Induces Concomitant SERTAD1, CDKN2B and GADD45A Modulation and Cellular Changes in Bladder Cancer Cells Regardless of the Site of TP53 Mutation.Pathology oncology research : POR · 2018Article
- Checkpoint kinase inhibitor AZD7762 strongly sensitises urothelial carcinoma cells to gemcitabine.Journal of experimental & clinical cancer research : CR · 2017Article
- Comprehensive analysis of aberrantly expressed profiles of lncRNAs and miRNAs with associated ceRNA network in muscle-invasive bladder cancer.Oncotarget · 2016Article
- Targeted therapies in bladder cancer: an overview of in vivo research.Nature reviews. Urology · 2015Review
- Invasive Bladder Cancer: Genomic Insights and Therapeutic Promise.Clinical cancer research : an official journal of the American Association for Cancer Research · 2015Review
- Upregulation of microRNA-96 and its oncogenic functions by targeting CDKN1A in bladder cancer.Cancer cell international · 2015Article
Corrections and comments
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.