ArticleJournal of hematology & oncology2014
CHK1 plays a critical role in the anti-leukemic activity of the wee1 inhibitor MK-1775 in acute myeloid leukemia cells.
Article in Journal of hematology & oncology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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Who cites it
37 citing papers in PubMed, 51 citations in OpenAlex.
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- Predicting response to hypomethylating agents in myeloid neoplasms: a robust model.Annals of hematology · 2026Article
- Enhancing the Nucleoside Analog Response with Translational Therapeutic Approaches to Overcome Resistance.Cells · 2026Review
- WEE Family Kinase Inhibitors Combined with Sorafenib Can Selectively Inhibit HCC Cell Proliferation.Current cancer drug targets · 2025Article
- Targeting ribonucleotide reductase to enhance the antileukemic activity of gilteritinib against chemoresistantASPET discovery · 2025Article
- Synergistic effect of adavosertib and fimepinostat on acute myeloid leukemia cells by enhancing the induction of DNA damage.Investigational new drugs · 2024Article
- Combined inhibition of Wee1 and Chk1 as a therapeutic strategy in multiple myeloma.Frontiers in oncology · 2023Article
- c-Myc plays a critical role in the antileukemic activity of the Mcl-1-selective inhibitor AZD5991 in acute myeloid leukemia.Apoptosis : an international journal on programmed cell death · 2022Article
- Molecular Threat of Splicing Factor Mutations to Myeloid Malignancies and Potential Therapeutic Modulations.Biomedicines · 2022Review
- Programmed cell death, redox imbalance, and cancer therapeutics.Apoptosis : an international journal on programmed cell death · 2021Review
- Targeting multiple signaling pathways: the new approach to acute myeloid leukemia therapy.Signal transduction and targeted therapy · 2020Review
- Pharmacological Inhibition of WEE1 Potentiates the Antitumoral Effect of theInternational journal of molecular sciences · 2020Article
- A WEE1 family business: regulation of mitosis, cancer progression, and therapeutic target.Journal of hematology & oncology · 2020Review
- Article
- Ubiquitination of the DNA-damage checkpoint kinase CHK1 by TRAF4 is required for CHK1 activation.Journal of hematology & oncology · 2020Article
- Inhibition of CDK9 by voruciclib synergistically enhances cell death induced by the Bcl-2 selective inhibitor venetoclax in preclinical models of acute myeloid leukemia.Signal transduction and targeted therapy · 2020Article
- The balance between mitotic death and mitotic slippage in acute leukemia: a new therapeutic window?Journal of hematology & oncology · 2019Review
- Article
- Inhibition of XPO1 enhances cell death induced by ABT-199 in acute myeloid leukaemia via Mcl-1.Journal of cellular and molecular medicine · 2018Article
Corrections and comments
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Authors and funding
9 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundAcute myeloid leukemia (AML) remains a difficult disease to treat and requires new therapies to improve treatment outcome. Wee1 inhibitors have been used to prevent activation of the G2 cell cycle checkpoint, thus enhancing the antitumor activity of DNA damaging agents. In this study, we investigated MK-1775 in AML cell lines and diagnostic blast samples to identify sensitive subtypes as well as possible mechanisms of resistance.
methodsIn vitro MK-1775 cytotoxicities of AML cell lines and diagnostic blasts were measured using MTT assays. The effects of MK-1775 on cell cycle progression and related proteins were determined by propidium iodide (PI) staining and flow cytometry analysis and Western blotting. Drug-induced apoptosis was determined using annexin V/PI staining and flow cytometry analysis.
resultsWe found that newly diagnosed and relapsed patient samples were equally sensitive to MK-1775. In addition, patient samples harboring t(15;17) translocation were significantly more sensitive to MK-1775 than non-t(15;17) samples. MK-1775 induced apoptosis in both AML cell lines and diagnostic blast samples, accompanied by decreased phosphorylation of CDK1 and CDK2 on Tyr-15 and increased DNA double-strand breaks (DSBs). Time-course experiments, using AML cell lines, revealed a time-dependent increase in DNA DSBs, activation of CHK1 and subsequent apoptosis following MK-1775 treatment, which could be attenuated by a CDK1/2 inhibitor, Roscovitine. Simultaneous inhibition of CHK1 and Wee1 resulted in synergistic anti-leukemic activity in both AML cell lines and primary patient samples ex vivo.
conclusionsOur study provides compelling evidence that CHK1 plays a critical role in the anti-leukemic activity of MK-1775 and highlights a possible mechanism of resistance to MK-1775. In addition, our study strongly supports the use of MK-1775 to treat both newly diagnosed and relapsed AML, especially cases with t(15;17) translocation, and supports the development of combination therapies with CHK1 inhibitors.
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