Reversal of malignant ADAR1 splice isoform switching with Rebecsinib

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

doi:10.1016/j.stem.2023.01.008

Reversal of malignant ADAR1 splice isoform switching with Rebecsinib

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

Authors

Leslie A Crews¹, Wenxue Ma², Luisa Ladel², Jessica Pham², Larisa Balaian¹, S Kathleen Steel², Phoebe K Mondala², Raymond H Diep², Christina N Wu², Cayla N Mason², Inge van der Werf², Isabelle Oliver², Eduardo Reynoso², Gabriel Pineda², Thomas C Whisenant³, Peggy Wentworth², James J La Clair⁴, Qingfei Jiang², Michael D Burkart⁴, Catriona H M Jamieson⁵

Affiliations

¹ 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.
² Department of Medicine, Division of Regenerative Medicine, Sanford Stem Cell Institute, University of California, San Diego, La Jolla, CA 92037, USA.
³ Center for Computational Biology & Bioinformatics (CCBB), Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
⁴ Departments of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA.
⁵ 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. Electronic address: cjamieson@health.ucsd.edu.

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.

Keywords: ADAR1; RNA editing; cancer stem cells; cancer therapy; hematopoiesis; leukemia stem cells; myelofibrosis; myeloproliferative neoplasms; secondary AML; splicing.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Adenosine Deaminase* / genetics
Animals
Hematopoietic Stem Cells*
Mice
Protein Isoforms

Substances

Protein Isoforms
Adenosine Deaminase
ADAR1 protein, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding