ArticleMolecular oncology2016
mTORC1 and DNA-PKcs as novel molecular determinants of sensitivity to Chk1 inhibition.
Article in Molecular oncology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 24 citations in OpenAlex.
- Polθ: emerging synthetic lethal partner in homologous recombination-deficient tumors.Cancer gene therapy · 2024Review
- Tumor biomarkers for diagnosis, prognosis and targeted therapy.Signal transduction and targeted therapy · 2024Review
- Chk1 inhibitor-induced DNA damage increases BFL1 and decreases BIM but does not protect human cancer cell lines from Chk1 inhibitor-induced apoptosis.American journal of cancer research · 2022Article
- Molecular regulation of lifespan extension in fertile ant workers.Philosophical transactions of the Royal Society of London. Series B, Biological sciences · 2021Article
- Targeting the PI3K/mTOR Pathway Augments CHK1 Inhibitor-Induced Replication Stress and Antitumor Activity in High-Grade Serous Ovarian Cancer.Cancer research · 2020Article
- Article
- A high content, high throughput cellular thermal stability assay for measuring drug-target engagement in living cells.PloS one · 2018Article
- Novel DNA targeted therapies for head and neck cancers: clinical potential and biomarkers.Oncotarget · 2017Review
- Regulation of CHK1 by mTOR contributes to the evasion of DNA damage barrier of cancer cells.Scientific reports · 2017Article
- Targeting the ATR-CHK1 Axis in Cancer Therapy.Cancers · 2017Review
- Tumour growth environment modulates Chk1 signalling pathways and Chk1 inhibitor sensitivity.Scientific reports · 2016Article
- mTORC1 and DNA-PKcs as novel molecular determinants of sensitivity to Chk1 inhibition.Molecular oncology · 2016Article
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
backgroundChk1 inhibitors are currently under clinical evaluation as single agents and in combination with cytotoxic chemotherapy. Understanding determinants of sensitivity and novel combinations is critical for further clinical development.
methodsPotentiation of mTOR inhibitor cytotoxicity by the Chk1 inhibitor V158411 was determined in p53 mutant colon cancer cells. DNA damage response, expression levels of repair proteins, cell cycle effects and the contribution of alternative DSB repair pathways were further evaluated by western blotting and high content analysis.
resultsmTOR inhibitors AZD8055, RAD-001, rapamycin and BEZ235 induced synergistic cytotoxicity with the Chk1 inhibitor V158411 in p53 mutant colon cancer cells. Reduced FANCD2, RAD51 and RPA70, core proteins in homologous recombination repair (HRR) and interstrand crosslink repair (ICLR), following inhibition of mTOR was associated with increased V158411 induced DSBs and caspase 3-independent cell death. Dual mTOR and Chk1 inhibition activated DNA-PKcs. Cells defective in DNA-PKcs exhibited increased resistance to V158411 with Chk1 expression closely correlated to DNA-PKcs expression in various types of cancer.
conclusionsDown regulation of proteins involved in HRR or ICLR by mTOR inhibitors is associated with increased sensitivity of human tumours to Chk1 inhibitors such as V158411. High levels of DNA-PKcs may be a potential biomarker to stratify patients to Chk1 inhibitor therapy alone or in combination with mTOR inhibitors.
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