TP53-agnostic lethality through combined pan-HDAC and CDK inhibition in acute myeloid leukemia.
(2025) Cancer Letters — Vol. 633, p. 218011 [1-17] (2025)
Files
2025_Pottier_Cancer_Lett.pdf
Open Access - Adobe PDF
- 14.29 MB
Details
- Authors
- Abstract
- (en) Tumor protein 53 (TP53)-mutated acute myeloid leukemia (AML) is characterized by poor outcomes and the quick development of treatment resistance. Here, we report that simultaneous inhibition of cyclin-dependent kinases (CDKs) and histone deacetylases (HDACs) with dinaciclib and CAY10603, respectively, eliminates the therapeutic response gap between TP53-mutant and TP53 wild-type AML. Biochemical profiling showed that CAY10603 is not only HDAC6-selective but also exhibits pan-HDAC activity similar to suberoylanilide hydroxamic acid, enabling dual targeting of transcriptional and cell cycle pathways. Across parental wild-type lines and isogenic TP53 mutants, the combination consistently suppressed clonogenic growth, induced caspase-dependent apoptosis, and downregulated key regulators such as CDK2, CDK4/6, and their cyclins, while restoring the CDK inhibitor CDKN1A/p21. In an orthotopic NSG mouse model, dinaciclib + CAY10603 significantly reduced leukemia burden and extended survival without adverse toxicity. By "normalizing" TP53-mutant AML to respond like its wild-type counterpart, this pan-HDAC/multi-CDK blockade offers a TP53-agnostic therapeutic option and warrants clinical evaluation as a strategy that remains effective regardless of baseline allelic status.
- Affiliations
UCLouvain SSS/IREC/2IP - IREC Imaging Platform (2IP)
Citations
Pottier, A., Park, S., Lee, Y., Liccardo, F., Yang, H., Park, J., Lorant, A., Schnekenburger, M., Brusa, D., Li, V., Valente, S., Mai, A., Skuli, S. J., Carroll, M., Boettcher, S., Sarry, J.-E., Cerella, C., Morceau, F., & Diederich, M. (2025). TP53-agnostic lethality through combined pan-HDAC and CDK inhibition in acute myeloid leukemia. Cancer Letters, 633, 218011 [1-17]. https://doi.org/10.1016/j.canlet.2025.218011 (Original work published 2025)