瑞贝昔布逆转恶性 ADAR1 剪接异构体转换。

Reversal of malignant ADAR1 splice isoform switching with Rebecsinib.

机构信息

Department of Medicine, Division of Regenerative Medicine, Sanford Stem Cell Institute, University of California, San Diego, La Jolla, CA 92037, USA; Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.

Department of Medicine, Division of Regenerative Medicine, Sanford Stem Cell Institute, University of California, San Diego, La Jolla, CA 92037, USA.

出版信息

Cell Stem Cell. 2023 Mar 2;30(3):250-263.e6. doi: 10.1016/j.stem.2023.01.008. Epub 2023 Feb 16.

DOI:10.1016/j.stem.2023.01.008

PMID:36803553

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10134781/

Abstract

Adenosine deaminase acting on RNA1 (ADAR1) preserves genomic integrity by preventing retroviral integration and retrotransposition during stress responses. However, inflammatory-microenvironment-induced ADAR1p110 to p150 splice isoform switching drives cancer stem cell (CSC) generation and therapeutic resistance in 20 malignancies. Previously, predicting and preventing ADAR1p150-mediated malignant RNA editing represented a significant challenge. Thus, we developed lentiviral ADAR1 and splicing reporters for non-invasive detection of splicing-mediated ADAR1 adenosine-to-inosine (A-to-I) RNA editing activation; a quantitative ADAR1p150 intracellular flow cytometric assay; a selective small-molecule inhibitor of splicing-mediated ADAR1 activation, Rebecsinib, which inhibits leukemia stem cell (LSC) self-renewal and prolongs humanized LSC mouse model survival at doses that spare normal hematopoietic stem and progenitor cells (HSPCs); and pre-IND studies showing favorable Rebecsinib toxicokinetic and pharmacodynamic (TK/PD) properties. Together, these results lay the foundation for developing Rebecsinib as a clinical ADAR1p150 antagonist aimed at obviating malignant microenvironment-driven LSC generation.

摘要

RNA 作用的腺苷脱氨酶 1（ADAR1）通过在应激反应中防止逆转录病毒整合和逆转录转座来维持基因组完整性。然而，炎症微环境诱导的 ADAR1p110 到 p150 剪接异构体转换驱动 20 种恶性肿瘤中的癌症干细胞（CSC）生成和治疗抵抗。以前，预测和预防 ADAR1p150 介导的恶性 RNA 编辑是一个重大挑战。因此，我们开发了慢病毒 ADAR1 和剪接报告基因，用于非侵入性检测剪接介导的 ADAR1 腺苷到肌苷（A-to-I）RNA 编辑激活；定量 ADAR1p150 细胞内流式细胞术分析；一种选择性的剪接介导的 ADAR1 激活的小分子抑制剂 Rebecsinib，它抑制白血病干细胞（LSC）自我更新，并在不影响正常造血干细胞和祖细胞（HSPCs）的剂量下延长人源化 LSC 小鼠模型的存活；以及 IND 前研究表明 Rebecsinib 具有良好的毒代动力学和药效学（TK/PD）特性。总之，这些结果为开发 Rebecsinib 作为临床 ADAR1p150 拮抗剂奠定了基础，旨在避免恶性微环境驱动的 LSC 生成。