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

Tamara B Garcia1, Rizvan C Uluisik2, Annemie A van Linden3

  • 1Medical Scientist Training Program, University of Colorado School of Medicine, Aurora, CO, United States.

Frontiers in Oncology
|March 21, 2020
PubMed

Insights

Resistance to WEE1 kinase inhibitors like AZD1775 in leukemia can be overcome. Increased histone deacetylase (HDAC) and MYC activity drive resistance, which can be reversed by inhibiting HDAC or BRD4.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • WEE1 kinase is a key regulator of the cell cycle and DNA damage response, making it a promising cancer therapeutic target.
  • AZD1775, a WEE1 inhibitor, is under investigation for cancer treatment, but acquired resistance is a significant challenge.

Purpose of the Study:

  • To investigate the mechanisms of acquired resistance to WEE1 inhibition by AZD1775 in acute leukemia.
  • To identify potential therapeutic strategies to overcome WEE1 inhibitor resistance.

Main Methods:

  • Developed AZD1775-resistant acute leukemia cell lines.
  • Assessed the role of histone deacetylase (HDAC) and KDM5A activity in resistant cells.
  • Analyzed gene expression changes, focusing on MYC and c-MYC.
  • Evaluated the efficacy of BRD4 inhibition in combination with AZD1775.

Main Results:

  • AZD1775-resistant cells showed dependence on increased HDAC activity, partly due to elevated KDM5A.
  • HDAC inhibition led to increased MYC expression and c-MYC activity in resistant cells.
  • Overexpression of c-MYC conferred AZD1775 resistance, which was partially reversed by BRD4 inhibition.

Conclusions:

  • Acquired resistance to WEE1 inhibition in leukemia involves increased HDAC and c-MYC activity.
  • Targeting HDAC or BRD4 may represent effective strategies to overcome AZD1775 resistance in leukemia.
Keywords:
AZD1775KDM5AWEE1adavosertibc-MYChistone deacetylase

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