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서울대학교

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Cancer Lett., Sep 01 2025, 633 S0304-3835(25)00581-6 | https://doi.org/10.1016/j.canlet.2025.218011 TP53-agnostic lethality through combined pan-HDAC and CDK inhibition in acute myeloid leukemia

Aurélien Pottier ^a, Sujung Park^b,1, Yejin Lee^b, Francesca Liccardo ^c, Haeun Yang ^b, Jeonghye Park^b, Anne Lorant ^a,2, Michael Schnekenburger ^a,3, Davide Brusa ^d, Vladimir Li ^b, Sergio Valente ^e, Antonello Mai^e, Sarah J. Skuli ^f, Martin Carroll ^f, Steffen Boettcher ^g, Jean-Emmanuel Sarry ^c, Claudia Cerella ^a,4, Franck Morceau ^a,5*, Marc Diederich^b**

^aLaboratoire de Biologie Moléculaire et Cellulaire du Cancer (LBMCC), 6A rue Nicolas-Ernest Barblé, L-1210, Luxembourg
^bResearch Institute of Pharmaceutical Sciences & Natural Products Research Institute, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea
^cEquipe Labellisée LIGUE 2023, Team Oncometabolism and drug resistance in Acute Myeloid Leukemia, Cancer Research Center of Toulouse, 2 Av. Hubert Curien, 31100, Toulouse, France
^dFlow Cytometry Platform, Université catholique de Louvain, B-1200, Bruxelles, Belgium
^eDepartment of Drug Chemistry and Technologies, La Sapienza University of Rome, Piazzale Aldo Moro 5, 00185, Rome, Italy
^fDivision of Hematology & Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
^gUniversitätsspital Zürich, Rämistrasse 100, CH-8091, Zürich, Switzerland

^*Corresponding author.
^**Corresponding author.
¹Catholic Hematology Hospital, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea.
²Luxembourg Centre for Systems Biomedicine, Bioinformatics Core, Roudeneck, 1, Boulevard du Jazz, L-4370 Esch-sur-Alzette, Luxembourg.
³Immune Endocrine Epigenetics Research Group, Department of Infection and Immunity, Luxembourg Institute of Health (LIH), 29 rue Henri Koch, L-4354 Esch-sur-Alzette, Luxembourg.
⁴Department of Cancer Research, Luxembourg Institute of Health (LIH), BAM Pavillon 2, 6A rue Nicolas-Ernest Barbl´e, L-1210 Luxembourg, Luxembourg.
⁵Department of Translational Medicine Operations Hub, Luxembourg Institute of Health (LIH), 1, rue Louis Rech, L-3555 Dudelange, Luxembourg. franck.

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.

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