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TP53-Agnostic Lethality through Combined Pan-HDAC and CDK Inhibition in Acute Myeloid Leukemia

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE305560 | GEO | 2025/12/02

REPOSITORIES: GEO

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Project description:Heart Failure with preserved Ejection Fraction (HFpEF) is a major global health problem but there are no effective therapies. The aim of this study was to assess the effects of histone deacetylase (HDAC) inhibition on cardiopulmonary structure, function, and metabolism in a large mammalian (feline) pressure overload model with HFpEF features. Male domestic short hair cats (n=26, aged 2mo), underwent either a sham procedure (n=5) or aortic constriction (n=21) using a pre-shaped band, resulting in slow-progressive pressure overload during subsequent growth. Two-months post-banding, banded cats were treated daily with either 10mg/kg suberoylanilide hydroxamic acid (b+SAHA) (n=8), an FDA approved pan-HDAC inhibitor, or vehicle (b+veh) (n=8) for 2 months. Echocardiography at 4-months post-banding revealed that b+SAHA animals had a significant reduction in left ventricular hypertrophy (LVH) and LA size vs b+veh animals. Invasively measured left ventricular end-diastolic pressure (LVEDP) and mean pulmonary arterial pressure (mPAP) were significantly elevated in b+veh and significantly reduced by b+SAHA. SAHA speeded ex-vivo myofibril relaxation independent of LVH and this effect correlated with in-vivo indices of LV relaxation. Furthermore, SAHA preserved lung structure, improved lung compliance and oxygenation, reflected by a decrease in alveolar-capillary wall thickness, alveolar-arterial oxygen gradient (A-aDO2), and intrapulmonary shunt. SAHA also reduced perivascular fluid cuffs around extra-alveolar vessels, suggesting attenuated alveolar-capillary stress failure. Acetylation proteomics revealed that SAHA altered protein acetylation in cat hearts, including histones, many mitochondrial metabolic enzymes involved in electron transport chain, TCA cycle, malate aspartate shuttle and beta oxidation, as well as cytoskeletal proteins important for muscle function. These results suggest that acetylation defects in hypertrophic stress states can be reversed by HDAC inhibitors and may be useful to improve cardiac structure and function in HFpEF patients.

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TP53-Agnostic Lethality through Combined Pan-HDAC and CDK Inhibition in Acute Myeloid Leukemia

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