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A MYC inhibitor selectively alters the MYC and MAX cistromes and modulates the epigenomic landscape to regulate

Austin G Holmes1, J Brandon Parker1, Vinay Sagar2

  • 1Division of Reproductive Sciences in Medicine, Department of Obstetrics and Gynecology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.

Science Advances
|April 27, 2022
PubMed

Insights

A novel MYC inhibitor, MYCi975, selectively targets cancer genes, sparing essential pathways. This drug combination therapy shows promise for treating resistant prostate and breast cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • MYC protein is a key regulator of gene expression implicated in various cancers.
  • Understanding the selectivity and downstream effects of MYC inhibitors is crucial for developing effective cancer therapies.

Purpose of the Study:

  • To investigate the effects of the small-molecule MYC inhibitor MYCi975 on MYC/MAX cistromes, epigenome, transcriptome, and tumorigenesis.
  • To elucidate the mechanisms underlying MYCi975's action and identify potential combination therapies.

Main Methods:

  • Integration of data from MYC/MAX cistrome, epigenome, and transcriptome analyses.
  • Assessment of MYCi975's impact on chromatin binding, accessibility, and H3K27 acetylation.
  • Evaluation of MYCi975 in combination with enzalutamide and 4-hydroxytamoxifen in cancer cell models.

Main Results:

  • MYCi975 modulated gene targets into three classes: down-regulated, up-regulated, and unaltered.
  • The inhibitor primarily affected cell cycle and signal transduction pathways, sparing RNA biogenesis and core transcriptional pathways.
  • MYCi975 suppressed MYC-regulated lineage factors AR/ARv7, FOXA1, and FOXM1, altering chromatin binding and accessibility.
  • MYCi975 synergistically sensitized resistant prostate cancer cells to enzalutamide and ER-positive breast cancer cells to 4-hydroxytamoxifen.

Conclusions:

  • MYCi975 demonstrates selective inhibition of MYC target gene expression.
  • The findings provide a mechanistic basis for using MYCi975 in combination therapies against MYC-driven cancers.
  • This approach offers a potential strategy to overcome resistance to existing cancer treatments.

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