NUC-7738 regulates β-catenin signalling resulting in reduced proliferation and self-renewal of AML cells

PLoS One. 2022 Dec 15;17(12):e0278209. doi: 10.1371/journal.pone.0278209. eCollection 2022.


Acute myeloid leukemia (AML) stem cells are required for the initiation and maintenance of the disease. Activation of the Wnt/β-catenin pathway is required for the survival and development of AML leukaemia stem cells (LSCs) and therefore, targeting β-catenin is a potential therapeutic strategy. NUC-7738, a phosphoramidate transformation of 3'-deoxyadenosine (3'-dA) monophosphate, is specifically designed to generate the active anti-cancer metabolite 3'-deoxyadenosine triphosphate (3'-dATP) intracellularly, bypassing key limitations of breakdown, transport, and activation. NUC-7738 is currently in a Phase I/II clinical study for the treatment of patients with advanced solid tumors. Protein expression and immunophenotypic profiling revealed that NUC-7738 caused apoptosis in AML cell lines through reducing PI3K-p110α, phosphorylated Akt (Ser473) and phosphorylated GSK3β (Ser9) resulting in reduced β-catenin, c-Myc and CD44 expression. NUC-7738 reduced β-catenin nuclear expression in AML cells. NUC-7738 also decreased the percentage of CD34+ CD38- CD123+ (LSC-like cells) from 81% to 47% and reduced the total number and size of leukemic colonies. These results indicate that therapeutic targeting of the PI3K/Akt/GSK3β axis can inhibit β-catenin signalling, resulting in reduced clonogenicity and eventual apoptosis of AML cells.

Publication types

  • Clinical Trial, Phase II
  • Clinical Trial, Phase I
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Cell Proliferation
  • Glycogen Synthase Kinase 3 beta / metabolism
  • Humans
  • Leukemia, Myeloid, Acute* / pathology
  • Neoplastic Stem Cells / pathology
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Wnt Signaling Pathway
  • beta Catenin* / metabolism


  • beta Catenin
  • Glycogen Synthase Kinase 3 beta
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt

Grants and funding

This study was supported by research funding from NuCana plc to all authors. The funders of this study were involved with the decision to publish and preparation of the manuscript.