TP53-agnostic lethality through combined pan-HDAC and CDK inhibition in acute myeloid leukemia

IF 10.1 1区医学 Q1 ONCOLOGY

Cancer letters Pub Date : 2025-09-01 DOI:10.1016/j.canlet.2025.218011

Aurélien Pottier , Sujung Park , Yejin Lee , Francesca Liccardo , Haeun Yang , Jeonghye Park , Anne Lorant , Michael Schnekenburger , Davide Brusa , Vladimir Li , Sergio Valente , Antonello Mai , Sarah J. Skuli , Martin Carroll , Steffen Boettcher , Jean-Emmanuel Sarry , Claudia Cerella , Franck Morceau , Marc Diederich

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引用次数: 0

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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泛hdac和CDK联合抑制急性髓系白血病tp53不可知致死率

肿瘤蛋白53 （Tumor protein 53, TP53）突变的急性髓性白血病（acute myeloid leukemia， AML）的特点是预后差，治疗耐药性发展快。在这里，我们报道了分别用dinaciclib和CAY10603同时抑制细胞周期蛋白依赖性激酶（CDKs）和组蛋白去乙酰化酶（hdac），消除了TP53突变型和TP53野生型AML之间的治疗反应差距。生化分析表明，CAY10603不仅具有hdac6选择性，而且具有类似亚甲基苯胺羟肟酸的泛hdac活性，能够双重靶向转录和细胞周期途径。在亲本野生型系和等基因TP53突变体中，该组合持续抑制克隆生长，诱导caspase依赖性细胞凋亡，下调关键调节因子如CDK2、CDK4/6及其细胞周期蛋白，同时恢复CDK抑制剂CDKN1A/p21。在原位NSG小鼠模型中，dinaciclib + CAY10603显著降低白血病负担，延长生存期，无不良毒性。通过使p53突变AML“正常化”，使其与野生型AML反应相似，这种泛hdac /多cdk阻断提供了一种与p53无关的治疗选择，并且值得临床评估，无论基线等位基因状态如何，该策略仍然有效。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cancer letters 医学-肿瘤学

CiteScore

17.70

自引率

2.10%

发文量

427

审稿时长

15 days

期刊介绍： Cancer Letters is a reputable international journal that serves as a platform for significant and original contributions in cancer research. The journal welcomes both full-length articles and Mini Reviews in the wide-ranging field of basic and translational oncology. Furthermore, it frequently presents Special Issues that shed light on current and topical areas in cancer research. Cancer Letters is highly interested in various fundamental aspects that can cater to a diverse readership. These areas include the molecular genetics and cell biology of cancer, radiation biology, molecular pathology, hormones and cancer, viral oncology, metastasis, and chemoprevention. The journal actively focuses on experimental therapeutics, particularly the advancement of targeted therapies for personalized cancer medicine, such as metronomic chemotherapy. By publishing groundbreaking research and promoting advancements in cancer treatments, Cancer Letters aims to actively contribute to the fight against cancer and the improvement of patient outcomes.