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WEE1 inhibition synergizes with CHOP chemotherapy and radiation therapy through induction of premature mitotic entry and DNA damage in diffuse large B-cell lymphoma

de Jong, M. R. W., Langendonk, M., Reitsma, B., Herbers, P., Lodewijk, M., Nijland, M., van den Berg, A., Ammatuna, E., Visser, L. & van Meerten, T., Jan-2020, In : Therapeutic advances in hematology. 11, p. 2040620719898373 14 p., 2040620719898373.

Research output: Contribution to journalArticleAcademicpeer-review

Background: Diffuse 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.

Methods: Cell 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.

Results: Treatment 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.

Conclusion: In 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.

Original languageEnglish
Article number2040620719898373
Pages (from-to)2040620719898373
Number of pages14
JournalTherapeutic advances in hematology
Volume11
Publication statusPublished - Jan-2020

    Keywords

  • AZD1775, CHOP, diffuse large B-cell lymphoma, radiation, WEE1, R-CHOP, RITUXIMAB, KINASE, MK-1775, CHK1, CYCLOPHOSPHAMIDE, IDENTIFICATION, REPLICATION, COMBINATION, SENSITIVITY

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