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Targeting epigenetic mechanisms to overcome venetoclax resistance

Gabriel Prado1, Charlotte L Kaestner1, Jonathan D Licht1

  • 1University of Florida Health Cancer Center and University of Florida Department of Medicine, Division of Hematology and Oncology, Gainesville, FL 32610, United States of America.

Biochimica Et Biophysica Acta. Molecular Cell Research
|May 4, 2021
PubMed

Insights

Venetoclax is a promising cancer drug, but resistance can occur. Epigenetic therapies, targeting DNA methylation and histone modification, show potential in overcoming this resistance in blood cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Venetoclax (a BCL2 inhibitor) is effective against hematologic malignancies by inducing apoptosis.
  • Therapy resistance to venetoclax can arise from increased MCL-1/BCL-XL expression or other mechanisms.
  • Overcoming venetoclax resistance is crucial for durable responses in cancer patients.

Purpose of the Study:

  • To review epigenetic strategies for overcoming venetoclax resistance in hematologic malignancies.
  • To explore how epigenetic modifiers can re-sensitize cancer cells to venetoclax.
  • To highlight the potential of combination therapies involving venetoclax and epigenetic agents.

Main Methods:

  • Review of recent preclinical and clinical studies on venetoclax resistance.
  • Analysis of epigenetic mechanisms contributing to therapy resistance.
  • Evaluation of novel epigenetic inhibitors (DNMT, HDAC, EZH2, BET inhibitors).

Main Results:

  • Epigenetic agents can target oncogenic gene expression driving venetoclax resistance.
  • Combination therapies of venetoclax with epigenetic drugs show efficacy in preclinical models.
  • Several epigenetic strategies are currently under investigation in clinical trials.

Conclusions:

  • Epigenetic modifications play a significant role in venetoclax resistance.
  • Targeting epigenetic mechanisms offers a promising strategy to enhance venetoclax efficacy.
  • Combination approaches hold potential for durable responses in hematologic cancers.
Keywords:
AzacytidineDecitabineEZH2JQ1Venetoclax

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