CHK1 plays a critical role in the anti-leukemic activity of the wee1 inhibitor MK-1775 in acute myeloid leukemia cells

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• 作者：Wenxiu Qi (1)
  Chengzhi Xie (1) (2) (3)
  Chunhuai Li (4)
  J Timothy Caldwell (5) (6)
  Holly Edwards (2) (3)
  Jeffrey W Taub (3) (7) (8)
  Yue Wang (4)
  Hai Lin (9)
  Yubin Ge (1) (2) (3)
  
  1. National Engineering Laboratory for AIDS Vaccine ; Key Laboratory for Molecular Enzymology & Engineering ; the Ministry of Education ; and School of Life Sciences ; Jilin University ; Changchun ; China
  2. Department of Oncology ; Wayne State University School of Medicine ; 110 East Warren Ave ; 48201 ; Detroit ; MI ; USA
  3. Molecular Therapeutics Program ; Barbara Ann Karmanos Cancer Institute ; Wayne State University School of Medicine ; 110 East Warren Ave ; Detroit ; MI ; USA
  4. Department of Pediatric Hematology and Oncology ; The First Hospital of Jilin University ; Changchun ; China
  5. MD/PhD Program ; Wayne State University School of Medicine ; 540 E. Canfield Ave ; Detroit ; MI ; USA
  6. Cancer Biology Program ; Wayne State University School of Medicine ; 110 East Warren Ave ; Detroit ; MI ; USA
  7. Department of Pediatrics ; Wayne State University School of Medicine ; 540 E. Canfield Ave ; Detroit ; MI ; USA
  8. Division of Pediatric Hematology/Oncology ; Children鈥檚 Hospital of Michigan ; 3901 Beaubien Blvd ; Detroit ; MI ; USA
  9. Department of Hematology and Oncology ; The First Hospital of Jilin University ; Changchun ; China
  
• 关键词：Wee1 ; MK ; 1775 ; CHK1 ; Acute myeloid leukemia
• 刊名：Journal of Hematology & Oncology
• 出版年：2014
• 出版时间：December 2014
• 年：2014
• 卷：7
• 期：1
• 全文大小：2,032 KB
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• 刊物主题：Oncology; Hematology; Cancer Research;
• 出版者：BioMed Central
• ISSN：1756-8722

文摘

Background Acute 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. Methods In 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. Results We 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. Conclusions Our 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.