Indisulam synergizes with palbociclib to induce senescence through inhibition of CDK2 kinase activity

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Updated: Aug 29, 2025

Through the Looking Glass: Time-lapse Microscopy and Longitudinal Tracking of Single Cells to Study Anti-cancer Therapeutics
06:00

Through the Looking Glass: Time-lapse Microscopy and Longitudinal Tracking of Single Cells to Study Anti-cancer Therapeutics

Published on: May 14, 2016

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Ziva Pogacar1, Jackie L Johnson1, Lenno Krenning2

  • 1Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands.

Plos One
|September 6, 2022
PubMed

Insights

Targeting cancer cells with CDK4/6 inhibitors like palbociclib can be enhanced by inhibiting CDK2. This combination therapy induces senescence and sensitizes cancer cells to senolytic treatments.

Area of Science:

  • Oncology
  • Cellular senescence
  • Drug discovery

Background:

  • Cellular senescence is a promising therapeutic strategy for cancer treatment.
  • Palbociclib, a CDK4/6 inhibitor, is approved for metastatic breast cancer but resistance can occur.
  • Enhancing senescence induction by CDK4/6 inhibitors is crucial for overcoming resistance.

Purpose of the Study:

  • To identify strategies for enhancing palbociclib-induced senescence.
  • To investigate the role of CDK2 in overcoming palbociclib resistance.
  • To evaluate the therapeutic potential of combined CDK4/6 and CDK2 inhibition.

Main Methods:

  • Functional genetic screens in palbociclib-resistant cancer cells.
  • Treatment with CDK2 inhibitor indisulam, alone and in combination with palbociclib.
  • Analysis of senescence induction, cell viability, and molecular markers (e.g., cyclin H).
  • Evaluation in various cancer cell lines and lung cancer xenografts.

Main Results:

  • Loss of CDK2 strongly enhanced senescence induction in palbociclib-treated cells.
  • Indisulam treatment phenocopied genetic CDK2 inactivation, inducing sustained senescence with palbociclib.
  • Indisulam downregulated cyclin H, inhibiting CDK2 activation.
  • Combined treatment induced senescence and sensitized cells to senolytic therapy.

Conclusions:

  • CDK2 inhibition via indisulam enhances senescence induction by CDK4/6 inhibitors.
  • The combination of palbociclib and indisulam represents a potential therapeutic strategy for enhancing cancer cell senescence.
  • This approach may improve sensitivity to senolytic therapies in cancer treatment.

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