PO.ET09.08 · 实验与分子治疗
靶向ADAR1 p150剪接活性的治疗在临床前研究中损伤CD44+ TNBC细胞群
Therapeutic targeting of ADAR1 p150 splicing activity impairs CD44 + TNBC cell populations in preclinical studies
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：三阴性乳腺癌（TNBC）由于缺乏靶向疗法以及存在耐药性肿瘤增殖细胞，在临床上仍具有挑战性。CD44和ADAR1促进TNBC的进展和治疗耐药。Rebecsinib是一种小分子抑制剂，旨在阻断剪接介导的ADAR1（作用于RNA的腺苷脱氨酶1）激活。本研究评估其在临床前人源化TNBC模型中选择性靶向CD44+和ADAR1+细胞的疗效。
方法：在Rag2-/- γc-/-和NSG-SGM3小鼠中建立了MDA-MB-231 TNBC细胞系衍生异种移植（CDX）模型。表达ADAR-nanoluciferase-GFP的MDA-MB-231细胞可通过IVIS成像追踪ADAR1活性。接受移植的小鼠给予载体、Rebecsinib静脉注射（10 mg/kg）或Rebecsinib口服（15 mg/kg），每周两次，持续两周。通过IVIS测量肿瘤负荷，并对外周血和组织（肺、肝、脾和骨髓）的单细胞悬液进行流式细胞术分析，以定量CD44+和ADAR1+细胞。
结果：在Rag2-/- γc-/-模型中，Rebecsinib显著减少了外周血（p < 0.05）、肺（p < 0.01）、肝（p < 0.01）和脾（p < 0.05）中的CD44+细胞（Student t检验）。在NSG-SGM3小鼠模型中，肺（p < 0.05）、肝（p < 0.01）和脾（p < 0.01）中的ADAR1+细胞也观察到相应减少（Student t检验）。IVIS成像显示Rebecsinib治疗组的肿瘤生物发光（p = 0.02，Student t检验）。与Fedratinib联合进一步抑制了肿瘤生长，提示协同效应（p < 0.05，Student t检验）。
结论：Rebecsinib选择性地减少CD44+和ADAR1+ TNBC细胞群，并在人源化临床前模型中抑制肿瘤进展。这些发现支持进一步评估Rebecsinib单独使用及联合使用作为TNBC的靶向治疗方法。
关键词：TNBC、ADAR1、CD44、Rebecsinib、靶向治疗、临床前模型。
查看英文原文 English abstract
Background: Triple-negative breast cancer (TNBC) remains clinically challenging due to the lack of targeted therapies and the presence of therapy-resistant tumor-propagating cells. CD44 and ADAR1 contribute to TNBC progression and therapeutic resistance. Rebecsinib is a small-molecule inhibitor designed to block splicing-mediated activation of ADAR1 (adenosine deaminase acting on RNA 1). This study evaluates its efficacy in selectively targeting CD44 + and ADAR1 + cells in preclinical humanized TNBC models.
Methods: MDA-MB-231 TNBC cell line-derived xenograft (CDX) models were established in Rag2 -/- gammac -/- and NSG-SGM3 mice. MDA-MB-231 ADAR-nanoluciferase-GFP expressing cells enable tracking of ADAR1 activity by IVIS imaging. Engrafted mice received vehicle, Rebecsinib IV (10 mg/kg), or Rebecsinib PO (15mg/kg), twice a week for two weeks. Tumor burden was measured by IVIS and single-cell suspensions from peripheral blood, and tissues (lung, liver, spleen, and bone marrow) were analyzed by flow cytometry to quantify CD44 + and ADAR1 + cells.
Results: Rebecsinib significantly reduced CD44 + cells in peripheral blood ( p < 0.05), lung ( p < 0.01), liver ( p < 0.01), and spleen ( p < 0.05) in Rag2 -/- gammac -/- models (Student t test). Corresponding decreases in ADAR1 + cells was observed in the lung (p < 0.05), liver (p < 0.01), and spleen (p < 0.01) in NSG-SGM3 mouse models ( S tudent t test). IVIS imaging demonstrated tumor bioluminescence in Rebecsinib-treated groups ( p = 0.02, student t test). Combination with Fedratinib further suppressed tumor growth, indicating a synergistic effect ( p < 0.05, student t test).
Conclusion: Rebecsinib selectively reduces CD44 + and ADAR1 + TNBC cell populations and inhibits tumor progression in humanized preclinical models. These findings support further evaluation of Rebecsinib alone and in combination, as a targeted therapeutic approach for TNBC.
Keywords: TNBC, ADAR1, CD44, Rebecsinib, targeted therapy, preclinical models.
利益披露 Disclosure
W. Ma, None..
J. Pham, None..
E. Klacking, None..
K. Wirtjes, None..
I. van der Werf, None..
P. Wentworth, None..
S. Morris, None..
J. La Clair, None..
M. Burkart, None..
C. Jamieson, None.