Abstract 7105: Therapeutic targeting of ADAR1 p150 splicing activity impairs CD44+ TNBC cell populations in preclinical studies

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-/-γc-/- 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-/-γc-/- 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 (Student 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. Citation Format: Wenxue Ma, Jessica Pham, Emma Klacking, Kendale Wirtjes, Inge van der Werf, Peggy Wentworth, Sheldon Morris, James La Clair, Michael Burkart, Catriona Jamieson. Therapeutic targeting of ADAR1 p150 splicing activity impairs CD44+ TNBC cell populations in preclinical studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7105.