| First Author | Crews LA | Year | 2023 |
| Journal | Cell Stem Cell | Volume | 30 |
| Issue | 3 | Pages | 250-263.e6 |
| PubMed ID | 36803553 | Mgi Jnum | J:350608 |
| Mgi Id | MGI:7446176 | Doi | 10.1016/j.stem.2023.01.008 |
| Citation | Crews LA, et al. (2023) Reversal of malignant ADAR1 splice isoform switching with Rebecsinib. Cell Stem Cell 30(3):250-263.e6 |
| abstractText | 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. |
