| Autor: |
Vincelette ND; Department of Molecular Pharmacology, Mayo Clinic, Rochester, MN, USA., Ding H; Division of Oncology Research, Mayo Clinic, Rochester, MN, USA., Huehls AM; Division of Oncology Research, Mayo Clinic, Rochester, MN, USA., Flatten KS; Division of Oncology Research, Mayo Clinic, Rochester, MN, USA., Kelly RL; Department of Molecular Pharmacology, Mayo Clinic, Rochester, MN, USA., Kohorst MA; Department of Pediatrics, Mayo Clinic, Rochester, MN, USA., Webster J; Sidney Kimmel Cancer Center at Johns Hopkins, Baltimore, MD, USA., Hess AD; Sidney Kimmel Cancer Center at Johns Hopkins, Baltimore, MD, USA., Pratz KW; Sidney Kimmel Cancer Center at Johns Hopkins, Baltimore, MD, USA., Karnitz LM; Department of Molecular Pharmacology, Mayo Clinic, Rochester, MN, USA. Karnitz.Larry@Mayo.edu.; Division of Oncology Research, Mayo Clinic, Rochester, MN, USA. Karnitz.Larry@Mayo.edu., Kaufmann SH; Department of Molecular Pharmacology, Mayo Clinic, Rochester, MN, USA. Kaufmann.Scott@Mayo.edu.; Division of Oncology Research, Mayo Clinic, Rochester, MN, USA. Kaufmann.Scott@Mayo.edu. |
| Abstrakt: |
CPX-351 is a liposomally encapsulated 5:1 molar ratio of cytarabine and daunorubicin that recently received regulatory approval for the treatment of therapy-related acute myeloid leukemia (AML) or AML with myelodysplasia-related changes based on improved overall survival compared to standard cytarabine/daunorubicin therapy. Checkpoint kinase 1 (CHK1), which is activated by DNA damage and replication stress, diminishes sensitivity to cytarabine and anthracyclines as single agents, suggesting that CHK1 inhibitors might increase the effectiveness of CPX-351. The present studies show that CPX-351 activates CHK1 as well as the S and G2/M cell cycle checkpoints. Conversely, CHK1 inhibition diminishes the cell cycle effects of CPX-351. Moreover, CHK1 knockdown or addition of a CHK1 inhibitor such as MK-8776, rabusertib or prexasertib enhances CPX-351-induced apoptosis in multiple TP53-null and TP53-wildtype AML cell lines. Likewise, CHK1 inhibition increases the antiproliferative effect of CPX-351 on primary AML specimens ex vivo, offering the possibility that CPX-351 may be well suited to combine with CHK1-targeted agents. |
