Publication

Increased HDAC Activity and c-MYC Expression Mediate Acquired Resistance to WEE1 Inhibition in Acute Leukemia

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Last modified
  • 05/21/2025
Type of Material
Authors
    Tamara B. Garcia, University of ColoradoRizvan C. Uluisik, Emory UniversityAnnemie A. van Linden, University of ColoradoKenneth L. Jones, University of ColoradoSujatha Venkataraman, University of ColoradoRajeev Vibhakar, University of ColoradoChristopher Porter, Emory University
Language
  • English
Date
  • 2020-03-05
Publisher
  • Frontiers Media S.A.
Publication Version
Copyright Statement
  • © 2020 Garcia, Uluisik, van Linden, Jones, Venkataraman, Vibhakar and Porter.
License
Final Published Version (URL)
Title of Journal or Parent Work
Volume
  • 10
Start Page
  • 296
End Page
  • 296
Grant/Funding Information
  • This work was supported by the National Institutes of Health, National Cancer Institute (CA172385 to CP), National Institute of Neurological Disorders and Stroke (NS031219 to RV), the University of Colorado Medical Scientist Training Program (GM008497), the Winship Cancer Institute (CA138292), and the University of Colorado Cancer Center (CA046934). AZD1775 was provided by Astra Zeneca.
Supplemental Material (URL)
Abstract
  • WEE1 is a cell cycle and DNA damage response kinase that is emerging as a therapeutic target for cancer. AZD1775 is a small molecule inhibitor of WEE1, currently in early phase clinical trials as a single agent and in combination with more conventional anti-neoplastic agents. As resistance to kinase inhibitors is frequent, we sought to identify mechanisms of resistance to WEE1 inhibition in acute leukemia. We found that AZD1775 resistant cell lines are dependent upon increased HDAC activity for their survival, in part due to increased KDM5A activity. In addition, gene expression analyses demonstrate HDAC dependent increase in MYC expression and c-MYC activity in AZD1775 treated resistant cells. Overexpression of c-MYC confers resistance to AZD1775 in cell lines with low baseline expression. Pharmacologic inhibition of BRD4, and thereby c-MYC, partially abrogated resistance to AZD1775. Thus, acquired resistance to WEE1 inhibition may be reversed by HDAC or BRD4 inhibition in leukemia cells.
Author Notes
Keywords
Research Categories
  • Health Sciences, Rehabilitation and Therapy
  • Health Sciences, Human Development
  • Biology, Genetics

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