Effect of CHK1 Inhibition on CPX-351 Cytotoxicity in vitro and ex vivo

Nicole D. Vincelette, Husheng Ding, Amelia M. Huehls, Karen S. Flatten, Rebecca L. Kelly, Mira A. Kohorst, Jonathan Webster, Allan D. Hess, Keith W. Pratz, Larry M Karnitz, Scott H Kaufmann

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Abstract

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.

Original languageEnglish (US)
Article number3617
JournalScientific reports
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2019

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Vincelette, N. D., Ding, H., Huehls, A. M., Flatten, K. S., Kelly, R. L., Kohorst, M. A., Webster, J., Hess, A. D., Pratz, K. W., Karnitz, L. M., & Kaufmann, S. H. (2019). Effect of CHK1 Inhibition on CPX-351 Cytotoxicity in vitro and ex vivo. Scientific reports, 9(1), [3617]. https://doi.org/10.1038/s41598-019-40218-0