ArticleTherapeutic advances in hematology2020
WEE1 inhibition synergizes with CHOP chemotherapy and radiation therapy through induction of premature mitotic entry and DNA damage in diffuse large B-cell lymphoma.
Article in Therapeutic advances in hematology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed, 15 citations in OpenAlex.
- Synthetic Lethal Combinations of DNA Repair Inhibitors and Genotoxic Agents to Target High-Risk Diffuse Large B Cell Lymphoma.Hematological oncology · 2025Article
- Targeting refractory diffuse large B cell lymphoma by CAR-WEE1 T-cells: In vitro evaluation.Annals of hematology · 2025Article
- Eukaryotic initiation factor 3a promotes the development of diffuse large B-cell lymphoma through regulating cell proliferation.BMC cancer · 2024Article
- Targeting the DNA damage response in hematological malignancies.Frontiers in oncology · 2024Review
- lncNBAT1/APOBEC3A is a mediator of HBX-induced chemoresistance in diffuse large B cell lymphoma cells.Molecular therapy. Nucleic acids · 2022Article
- Interaction between ERAP Alleles and HLA Class I Types Support a Role of Antigen Presentation in Hodgkin Lymphoma Development.Cancers · 2021Article
- A WEE1 family business: regulation of mitosis, cancer progression, and therapeutic target.Journal of hematology & oncology · 2020Review
- TEOA Inhibits Proliferation and Induces DNA Damage of Diffuse Large B-Cell Lymphoma Cells Through Activation of the ROS-Dependent p38 MAPK Signaling Pathway.Frontiers in pharmacology · 2020Article
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Authors and funding
10 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundDiffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease, characterized by high levels of genomic instability and the activation of DNA damage repair pathways. We previously found high expression of the cell cycle regulator WEE1 in DLBCL cell lines. Here, we investigated the combination of the WEE1 inhibitor, AZD1775, with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) and radiation therapy (RT), with the aim of improving first-line treatment.
methodsCell viability experiments were performed to determine synergistic combinations. Levels of DNA damage were established using flow cytometry for γH2AX and protein analysis for DNA damage response proteins CHK1 and CHK2. Flow cytometry analysis for cell cycle and pH3 were performed to determine cell cycle distribution and premature mitotic entry.
resultsTreatment with either RT or CHOP led to enhanced sensitivity to AZD1775 in several DLBCL cell lines. Treatment of cells with AZD1775 induced unscheduled mitotic progression, resulting in abnormal cell cycle distribution in combination with RT or CHOP treatment. In addition, a significant increase in DNA damage was observed compared with CHOP or RT alone. Of the single CHOP components, doxorubicin showed the strongest effect together with AZD1775, reducing viability and increasing DNA damage.
conclusionIn conclusion, the combination of RT or CHOP with AZD1775 enhances sensitivity to WEE1 inhibition through unscheduled G2/M progression, leading to increased DNA damage. Based on these results, WEE1 inhibition has great potential together with other G2/M arresting or DNA damaging (chemo) therapeutic compounds and should be further explored in clinical trials.
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