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TP53 upregulation via aurora kinase inhibition overcomes primary failure to venetoclax in BCL2-rearranged lymphomas

IF 4.6 2区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

iScience Pub Date : 2025-05-02 DOI:10.1016/j.isci.2025.112584

Rajeswaran Mani , Samon Benrashid , Margaret D. Templeton , Lawrence J. Druhan , Sara L. Seegers , Supriya Chakraborty , Sarah E. Teague , Scott C. Jaros , Hsih-Te Yang , David M. Foureau , Nury M. Steuerwald , Dhananjaya Pal , Nilanjan Ghosh , Edward A. Copelan , Donald L. Durden , Belinda R. Avalos , Steven I. Park

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引用次数: 0

Abstract

Bcl2 inhibition has excellent antitumor activity against hematologic malignancies. However, the clinical results in lymphomas harboring BCL2 gene rearrangements have been disappointing, and the mechanism of this intrinsic resistance remains unknown. Herein, we report that Bcl2 inhibition rapidly repressed p53 with poor response in BCL2-rearranged lymphoma cells. However, concurrent inhibition of aurora kinase (Aurk) overcame this primary resistance to Bcl2 inhibition by restoring the p53/p21 proapoptotic axis via a post-transcriptional increase in p53. Two independent BCL2-rearranged lymphoma murine models showed complete tumor regression in all animals treated with combined Bcl2/Aurk inhibition, whereas mice treated with single-agents demonstrated rapid progression. Transcriptome analysis confirmed that BCL2-rearranged lymphomas rapidly downregulated the p53 target CDKN1A (p21) in response to Bcl2 inhibition in vivo. However, concurrent inhibition of Aurk restored the TP53/CDKN1A pathway, sensitizing the tumors to Bcl2 inhibitor-mediated apoptosis. These data lay the groundwork for evaluation of this combination in the clinical setting.

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通过极光激酶抑制的TP53上调克服了bcl2重排淋巴瘤中venetoclax的主要失败

抑制Bcl2对血液系统恶性肿瘤具有良好的抗肿瘤活性。然而，含有BCL2基因重排的淋巴瘤的临床结果令人失望，而且这种内在耐药性的机制仍不清楚。在此，我们报道Bcl2抑制快速抑制p53，但在Bcl2重排淋巴瘤细胞中反应不佳。然而，极光激酶（Aurk）的并发抑制通过p53转录后增加来恢复p53/p21促凋亡轴，从而克服了对Bcl2抑制的最初抗性。两种独立的Bcl2重排淋巴瘤小鼠模型在Bcl2/Aurk联合抑制治疗的所有动物中均显示肿瘤完全消退，而单药治疗的小鼠则表现出快速进展。转录组分析证实，Bcl2重排淋巴瘤在体内响应Bcl2抑制，迅速下调p53靶点CDKN1A （p21）。然而，同时抑制Aurk恢复了TP53/CDKN1A通路，使肿瘤对Bcl2抑制剂介导的细胞凋亡敏感。这些数据为在临床环境中评估这种组合奠定了基础。

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

iScience

iScience Multidisciplinary-Multidisciplinary

CiteScore

7.20

自引率

1.70%

发文量

1972

审稿时长

6 weeks

期刊介绍： Science has many big remaining questions. To address them, we will need to work collaboratively and across disciplines. The goal of iScience is to help fuel that type of interdisciplinary thinking. iScience is a new open-access journal from Cell Press that provides a platform for original research in the life, physical, and earth sciences. The primary criterion for publication in iScience is a significant contribution to a relevant field combined with robust results and underlying methodology. The advances appearing in iScience include both fundamental and applied investigations across this interdisciplinary range of topic areas. To support transparency in scientific investigation, we are happy to consider replication studies and papers that describe negative results. We know you want your work to be published quickly and to be widely visible within your community and beyond. With the strong international reputation of Cell Press behind it, publication in iScience will help your work garner the attention and recognition it merits. Like all Cell Press journals, iScience prioritizes rapid publication. Our editorial team pays special attention to high-quality author service and to efficient, clear-cut decisions based on the information available within the manuscript. iScience taps into the expertise across Cell Press journals and selected partners to inform our editorial decisions and help publish your science in a timely and seamless way.

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