Résumé
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.
•CAY10603 is a bona fide pan-HDAC inhibitor, not HDAC6-selective.•Dual HDAC/CDK blockade restores TP53-mutant AML to wild-type response.•Synergy confirmed by Chou–Talalay at sub-IC50 doses.•In vivo combo reduces AML burden and prolongs survival without toxicity.