ArticleNeoplasia (New York, N.Y.)2022
Inhibition of DNA-PK may improve response to neoadjuvant chemoradiotherapy in rectal cancer.
Article in Neoplasia (New York, N.Y.), 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 21 citations in OpenAlex.
- Review
- Medicinal chemistry breakthroughs on ATM, ATR, and DNA-PK inhibitors as prospective cancer therapeutics.Journal of enzyme inhibition and medicinal chemistry · 2025Review
- DNA-PK Inhibition Shows Differential Radiosensitization in Orthotopic GBM PDX Models Based on DDR Pathway Deficits.Molecular cancer therapeutics · 2025Article
- HPV and p53 Status as Precision Determinants of Head and Neck Cancer Response to DNA-PKcs Inhibition in Combination with Irradiation.Molecular cancer therapeutics · 2025Article
- Radioresistance in rectal cancer: can nanoparticles turn the tide?Molecular cancer · 2025Review
- Titin gene mutations enhance radiotherapy efficacy via modulation of tumour immune microenvironment in rectum adenocarcinoma.Clinical and translational medicine · 2025Article
- Enhancing Standard of Care Chemotherapy Efficacy Using DNA-Dependent Protein Kinase (DNA-PK) Inhibition in Preclinical Models of Ewing Sarcoma.Molecular cancer therapeutics · 2024Article
- Identification and Validation of New DNA-PKcs Inhibitors through High-Throughput Virtual Screening and Experimental Verification.International journal of molecular sciences · 2024Article
- Differential Distribution of the DNA-PKcs Inhibitor Peposertib Selectively Radiosensitizes Patient-derived Melanoma Brain Metastasis Xenografts.Molecular cancer therapeutics · 2024Article
- Artemis as Predictive Biomarker of Responsiveness to Preoperative Chemoradiotherapy in Patients with Locally Advanced Rectal Cancer.Current oncology (Toronto, Ont.) · 2024Article
- Effect of FOLFOX regimen combined with cetuximab treatment on the efficacy and tumor markers of advanced colon cancer patients.American journal of translational research · 2024Article
- Review
- Targeting the DNA damage response for cancer therapy.Biochemical Society transactions · 2023Article
- A genome-wide CRISPR/Cas9 screen identifies DNA-PK as a sensitiser toTheranostics · 2023Article
- Targeting the DNA Damage Response and DNA Repair Pathways to Enhance Radiosensitivity in Colorectal Cancer.Cancers · 2022Review
- Targeting Histone Epigenetic Modifications and DNA Damage Responses in Synthetic Lethality Strategies in Cancer?Cancers · 2022Article
- Development and Evolution of DNA-Dependent Protein Kinase Inhibitors toward Cancer Therapy.International journal of molecular sciences · 2022Review
Corrections and comments
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Authors and funding
11 authors at 2 institutions in 1 country.
Funding
Abstract
Treatment of locally advanced rectal cancer includes chemoradiation and surgery, but patient response to treatment is variable. Patients who have a complete response have improved outcomes; therefore, there is a critical need to identify mechanisms of resistance to circumvent them. DNA-PK is involved in the repair of DNA double-strand breaks caused by radiation, which we found to be increased in rectal cancer after treatment. We hypothesized that inhibiting this complex with a DNA-PK inhibitor, Peposertib (M3814), would improve treatment response. We assessed pDNA-PK in a rectal cancer cell line and mouse model utilizing western blotting, viability assays, γH2AX staining, and treatment response. The three treatment groups were: standard of care (SOC) (5-fluorouracil (5FU) with radiation), M3814 with radiation, and M3814 with SOC. SOC treatment of rectal cancer cells increased pDNA-PK protein and increased γH2AX foci, but this was abrogated by the addition of M3814. Mice with CT26 tumors treated with M3814 with SOC did not differ in average tumor size but individual tumor response varied. The clinical complete response rate improved significantly with the addition of M3814 but pathological complete response did not. We investigated alterations in DNA repair and found that Kap1 and pATM are increased after M3814 addition suggesting this may mediate resistance. When the DNA-PK inhibitor, M3814, is combined with SOC treatment, response improved in some rectal cancer models but an increase in other repair mechanisms likely diminishes the effect. A clinical trial is ongoing to further explore the role of DNA-PK inhibition in rectal cancer treatment.
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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.