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A Data Integration Workflow to Identify Drug Combinations Targeting Synthetic Lethal Interactions
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Published on: May 27, 2021

Synthetic lethal targeting of MYC by activation of the DR5 death receptor pathway

Yan Wang1, Ingo H Engels, Deborah A Knee

  • 1Department of Cancer Biology, Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121 USA.

Cancer Cell
|May 18, 2004
PubMed

Insights

Targeting the MYC oncogene with DR5 agonists induces cancer cell death. This approach leverages synthetic lethality for MYC-selective cancer therapeutics, showing promise in preclinical models.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Synthetic lethality offers a strategy for developing genotype-selective anticancer drugs.
  • This approach targets physiological changes from oncogene activation or tumor suppressor loss for tumor selectivity.

Purpose of the Study:

  • To investigate the efficacy of TRAIL death receptor DR5 agonists against MYC-overexpressing human cancers.
  • To elucidate the molecular mechanisms underlying MYC-induced sensitization to DR5 agonists.

Main Methods:

  • In vitro apoptosis assays in human cancer cell lines.
  • In vivo studies using tumor xenografts in preclinical models.
  • Analysis of DR5 cell surface expression and procaspase-8 processing.

Main Results:

  • DR5 agonists induced potent apoptosis in MYC-overexpressing cells, both in vitro and in vivo.
  • MYC sensitized cells to DR5 agonists via a p53-independent pathway.
  • Upregulation of DR5 cell surface levels and enhanced procaspase-8 processing were observed.

Conclusions:

  • MYC sensitizes cancer cells to apoptosis through a novel mechanism involving DR5.
  • DR5 agonists represent a promising therapeutic strategy for MYC-driven cancers.

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