Reversal of malignant ADAR1 splice isoform switching with Rebecsinib.

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.

• Authors: Leslie A Crews, Wenxue Ma, Luisa Ladel, Jessica Pham, Larisa Balaian, S Kathleen Steel, Phoebe K Mondala, Raymond H Diep, Christina N Wu, Cayla N Mason, Inge van der Werf, Isabelle Oliver, Eduardo Reynoso, Gabriel Pineda, Thomas C Whisenant, Peggy Wentworth, James J La Clair, Qingfei Jiang, Michael D Burkart, Catriona H M Jamieson
• Journal: Cell stem cell (Cell Stem Cell) Vol. 30 Issue 3 Pg. 250-263.e6 (03 02 2023) ISSN: 1875-9777 [Electronic] United States
• PMID: 36803553 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Protein Isoforms
• Adenosine Deaminase
• ADAR1 protein, mouse

Topics

• Mice
• Animals
• Protein Isoforms
• Hematopoietic Stem Cells
• Adenosine Deaminase (genetics)