ArticleInternational journal of cancer2019
Targeting the TLK1/NEK1 DDR axis with Thioridazine suppresses outgrowth of androgen independent prostate tumors.
Article in International journal of cancer, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 49 citations in OpenAlex.
- NEK1 Promotes Ovarian Cancer Progression via p53 Suppression While Enhancing Sensitivity to Genotoxic Therapy.Current issues in molecular biology · 2026Article
- Phenothiazine Derivatives and Their Impact on the Apoptosis Processes: A Review.Journal of applied toxicology : JAT · 2026Review
- Studies on the functionality of the TC-NER ERCC6-M1097V protein variant frequently found in Louisiana patients with PCa upon UV damage.Frontiers in oncology · 2025Article
- The NIMA-related kinase family and cancer.Frontiers in oncology · 2025Review
- ALS-associated C21ORF2 variant disrupts DNA damage repair, mitochondrial metabolism, neuronal excitability and NEK1 levels in human motor neurons.Acta neuropathologica communications · 2024Article
- Article
- Review
- Exploiting TLK1 and Cisplatin Synergy for Synthetic Lethality in Androgen-Insensitive Prostate Cancer.Biomedicines · 2023Article
- Differential Expression of NEK Kinase Family Members in Esophageal Adenocarcinoma and Barrett's Esophagus.Cancers · 2023Article
- TLK1-mediated RAD54 phosphorylation spatio-temporally regulates Homologous Recombination Repair.Nucleic acids research · 2023Article
- Untousling the Role of Tousled-like Kinase 1 in DNA Damage Repair.International journal of molecular sciences · 2023Review
- Targeting Prostate Cancer, the 'Tousled Way'.International journal of molecular sciences · 2023Review
- The NEK family of serine/threonine kinases as a biomarker for cancer.Clinical and experimental medicine · 2023Review
- Androgen Deprivation Freezes Hormone-Sensitive Prostate Cancer Cells in a Reversible, Genetically Unstable Quasi-Apoptotic State, Bursting into Full Apoptosis upon Poly(ADP-ribose) Polymerase Inhibition.International journal of molecular sciences · 2023Article
- Identification of biological pathways and processes regulated by NEK5 in breast epithelial cells via an integrated proteomic approach.Cell communication and signaling : CCS · 2022Article
- The TLK1-MK5 Axis Regulates Motility, Invasion, and Metastasis of Prostate Cancer Cells.Cancers · 2022Article
- TLK1-mediated MK5-S354 phosphorylation drives prostate cancer cell motility and may signify distinct pathologies.Molecular oncology · 2022Article
- The functions, oncogenic roles, and clinical significance of circular RNAs in renal cell carcinoma.Medical oncology (Northwood, London, England) · 2022Review
- The spectrum of sex differences in cancer.Trends in cancer · 2022Review
- Tousled-like kinase 1: a novel factor with multifaceted role in mCRPC progression and development of therapy resistance.Cancer drug resistance (Alhambra, Calif.) · 2022Review
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Standard therapy for advanced Prostate Cancer (PCa) consists of antiandrogens, which provide respite from disease progression, but ultimately fail resulting in the incurable phase of the disease: mCRPC. Targeting PCa cells before their progression to mCRPC would greatly improve the outcome. Combination therapy targeting the DNA Damage Response (DDR) has been limited by general toxicity, and a goal of clinical trials is how to target the DDR more specifically. We now show that androgen deprivation therapy (ADT) of LNCaP cells results in increased expression of TLK1B, a key kinase upstream of NEK1 and ATR and mediating the DDR that typically results in a temporary cell cycle arrest of androgen responsive PCa cells. Following DNA damage, addition of the TLK specific inhibitor, thioridazine (THD), impairs ATR and Chk1 activation, establishing the existence of a ADT > TLK1 > NEK1 > ATR > Chk1, DDR pathway, while its abrogation leads to apoptosis. Treatment with THD suppressed the outgrowth of androgen-independent (AI) colonies of LNCaP and TRAMP-C2 cells cultured with bicalutamide. Moreover, THD significantly inhibited the growth of several PCa cells in vitro (including AI lines). Administration of THD or bicalutamide was not effective at inhibiting long-term tumor growth of LNCaP xenografts. In contrast, combination therapy remarkably inhibited tumor growth via bypass of the DDR. Moreover, xenografts of LNCaP cells overexpressing a NEK1-T141A mutant were durably suppressed with bicalutamide. Collectively, these results suggest that targeting the TLK1/NEK1 axis might be a novel therapy for PCa in combination with standard of care (ADT).
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Registered trials
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.