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Reversal of malignant ADAR1 splice isoform switching with Rebecsinib

Leslie A Crews1, Wenxue Ma2, Luisa Ladel2

  • 1Department 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.

Cell Stem Cell
|February 21, 2023
PubMed

Insights

Adenosine deaminase acting on RNA1 (ADAR1) promotes cancer by altering RNA editing. A new inhibitor, Rebecsinib, effectively targets this process in leukemia stem cells, offering a promising therapeutic strategy.

Area of Science:

  • Molecular Biology
  • Oncology
  • Genetics

Background:

  • Adenosine deaminase acting on RNA1 (ADAR1) is crucial for genomic stability, preventing retroviral elements during stress.
  • Aberrant ADAR1 splicing (ADAR1p110 to p150) in inflammatory environments drives cancer stem cell (CSC) generation and treatment resistance in numerous cancers.
  • Targeting ADAR1p150-mediated RNA editing has been a significant challenge in cancer therapy.

Purpose of the Study:

  • To develop methods for detecting and inhibiting ADAR1p150-mediated RNA editing in cancer.
  • To evaluate the efficacy of a novel small-molecule inhibitor, Rebecsinib, against leukemia stem cells (LSCs).

Main Methods:

  • Development of lentiviral reporters for non-invasive detection of ADAR1 RNA editing.
  • Establishment of a quantitative flow cytometric assay for ADAR1p150.
  • In vitro and in vivo testing of Rebecsinib in LSC and humanized mouse models.
  • Pre-IND toxicokinetic and pharmacodynamic studies of Rebecsinib.

Main Results:

  • Successful development of reporters and assays for ADAR1 RNA editing detection.
  • Rebecsinib demonstrated inhibition of LSC self-renewal and prolonged survival in LSC mouse models.
  • Rebecsinib exhibited favorable toxicokinetic and pharmacodynamic properties in pre-IND studies.
  • Rebecsinib selectively targeted LSCs while sparing normal hematopoietic stem and progenitor cells (HSPCs).

Conclusions:

  • The developed tools enable non-invasive monitoring of ADAR1 RNA editing activation.
  • Rebecsinib is a potent inhibitor of splicing-mediated ADAR1 activation, targeting LSC generation.
  • Rebecsinib shows promise as a clinical candidate for treating malignancies driven by ADAR1p150.
Keywords:
ADAR1RNA editingcancer stem cellscancer therapyhematopoiesisleukemia stem cellsmyelofibrosismyeloproliferative neoplasmssecondary AMLsplicing

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