The multi-CDK inhibitor dinaciclib reverses bromo- and extra-terminal domain (BET) inhibitor resistance in acute myeloid leukemia via inhibition of Wnt/β-catenin signaling.

Autor: Marr AR; Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA., Halpin M; Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA., Corbin DL; Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA., Asemelash Y; Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA., Sher S; Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA., Gordon BK; Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA., Whipp EC; Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA., Mitchell S; Department of Pathology, Stanford University, Stanford, CA, USA., Harrington BK; College of Veterinary Medicine, Michigan State University, Lansing, MI, USA., Orwick S; Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA., Benrashid S; Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA., Goettl VM; Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA., Yildiz V; Department of Biomedical Informatics, The Ohio State University, Columbus, OH, USA., Mitchell AD; Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA., Cahn O; Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA., Mims AS; Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA., Larkin KTM; Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA., Long M; Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA., Blachly J; Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.; Leukemia Research Program, The Ohio State University James Comprehensive Cancer Center, Columbus, OH, USA., Woyach JA; Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.; Leukemia Research Program, The Ohio State University James Comprehensive Cancer Center, Columbus, OH, USA., Lapalombella R; Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.; Leukemia Research Program, The Ohio State University James Comprehensive Cancer Center, Columbus, OH, USA., Grieselhuber NR; Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA. Nicole.Grieselhuber@osumc.edu.; Leukemia Research Program, The Ohio State University James Comprehensive Cancer Center, Columbus, OH, USA. Nicole.Grieselhuber@osumc.edu.
Jazyk: angličtina
Zdroj: Experimental hematology & oncology [Exp Hematol Oncol] 2024 Mar 04; Vol. 13 (1), pp. 27. Date of Electronic Publication: 2024 Mar 04.
DOI: 10.1186/s40164-024-00483-w
Abstrakt: Acute myeloid leukemia (AML) is a highly aggressive hematologic cancer with poor survival across a broad range of molecular subtypes. Development of efficacious and well-tolerable therapies encompassing the range of mutations that can arise in AML remains an unmet need. The bromo- and extra-terminal domain (BET) family of proteins represents an attractive therapeutic target in AML due to their crucial roles in many cellular functions, regardless of any specific mutation. Many BET inhibitors (BETi) are currently in pre-clinical and early clinical development, but acquisition of resistance continues to remain an obstacle for the drug class. Novel methods to circumvent this development of resistance could be instrumental for the future use of BET inhibitors in AML, both as monotherapy and in combination. To date, many investigations into possible drug combinations of BETi with CDK inhibitors have focused on CDK9, which has a known physical and functional interaction with the BET protein BRD4. Therefore, we wished to investigate possible synergy and additive effects between inhibitors of these targets in AML. Here, we describe combination therapy with the multi-CDK inhibitor dinaciclib and the BETi PLX51107 in pre-clinical models of AML. Dinaciclib and PLX51107 demonstrate additive effects in AML cell lines, primary AML samples, and in vivo. Further, we demonstrate novel activity of dinaciclib through inhibition of the canonical/β-catenin dependent Wnt signaling pathway, a known resistance mechanism to BETi in AML. We show dinaciclib inhibits Wnt signaling at multiple levels, including downregulation of β-catenin, the Wnt co-receptor LRP6, as well as many Wnt pathway components and targets. Moreover, dinaciclib sensitivity remains unaffected in a setting of BET resistance, demonstrating similar inhibitory effects on Wnt signaling when compared to BET-sensitive cells. Ultimately, our results demonstrate rationale for combination CDKi and BETi in AML. In addition, our novel finding of Wnt signaling inhibition could have potential implications in other cancers where Wnt signaling is dysregulated and demonstrates one possible approach to circumvent development of BET resistance in AML.
(© 2024. The Author(s).)
Databáze: MEDLINE
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