Related Experiment Video

Updated: Aug 20, 2025

Simultaneous Imaging and Flow-Cytometry-based Detection of Multiple Fluorescent Senescence Markers in Therapy-Induced Senescent Cancer Cells
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Simultaneous Imaging and Flow-Cytometry-based Detection of Multiple Fluorescent Senescence Markers in Therapy-Induced Senescent Cancer Cells

Published on: July 12, 2022

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cFLIP suppression and DR5 activation sensitize senescent cancer cells to senolysis

Liqin Wang1, Haojie Jin2,3, Fleur Jochems2

  • 1Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands. l.wang@nki.nl.

Nature Cancer
|November 22, 2022
PubMed

Insights

Senolytics can enhance cancer therapy by targeting senescent cells. Researchers found that inhibiting cFLIP, a death receptor inhibitor, makes senescent cancer cells vulnerable to death receptor 5 (DR5) activation.

Area of Science:

  • Oncology
  • Cellular Biology
  • Pharmacology

Background:

  • Senolytics aim to improve cancer therapy by eliminating senescent cells.
  • Current senolytic drugs lack broad efficacy, posing a challenge for combination therapies.

Purpose of the Study:

  • Identify common vulnerabilities in senescent cancer cells.
  • Develop a broadly effective senolytic strategy to enhance pro-senescence cancer therapies.

Main Methods:

  • CRISPR/Cas9 genetic screens in senescent cancer cell models.
  • Investigated the role of cFLIP in senescent cell survival.
  • Utilized DR5 agonistic antibodies and BRD2 inhibition.
  • Validated findings in animal models.

Main Results:

  • Loss of cFLIP (cellular FLICE-inhibitory protein) is a common vulnerability in senescent cancer cells.
  • NF-κB pathway upregulates DR5 and TRAIL, priming senescent cells for apoptosis.
  • Increased cFLIP expression protects senescent cells from death.
  • DR5 activation, enhanced by cFLIP suppression (e.g., via BRD2 inhibition), efficiently kills senescent cancer cells.
  • Senescent cells induce bystander killing of non-senescent cells via cytokine secretion.
  • Combined pro-senescence therapy and DR5 activation show efficacy in animal models.

Conclusions:

  • Targeting cFLIP enhances senolytic efficacy against cancer cells.
  • A 'one-two punch' approach combining pro-senescence therapy with DR5 activation is a promising strategy.
  • This approach offers a novel therapeutic avenue for cancer treatment.

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