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

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Date
15/12/2022
Author
Shahid, Muhammed Akbar
Um, In Hwa
Elshani, Mustafa
Zhang, Ying
Harrison, David James
Keywords
RC0254 Neoplasms. Tumors. Oncology (including Cancer)
NDAS
MCC
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Abstract
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.
Citation
Shahid , M A , Um , I H , Elshani , M , Zhang , Y & Harrison , D J 2022 , ' NUC-7738 regulates β-catenin signalling resulting in reduced proliferation and self-renewal of AML cells ' , PLoS ONE , vol. 17 , no. 12 , e0278209 . https://doi.org/10.1371/journal.pone.0278209
Publication
PLoS ONE
Status
Peer reviewed
DOI
https://doi.org/10.1371/journal.pone.0278209
ISSN
1932-6203
Type
Journal article
Rights
Copyright: © 2022 Shahid et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Description
Funding: This study was supported by research funding from NuCana plc to all authors.
Collections
  • University of St Andrews Research
URI
http://hdl.handle.net/10023/26617

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