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Pharmacological CDK4/6 inhibition promotes vulnerability to lysosomotropic agents in breast cancer

Jamil Nehme1, Sjors Maassen1, Sara Bravaccini2

  • 1European Research Institute for the Biology of Ageing (ERIBA), University Medical Center Groningen (UMCG), University of Groningen (RUG), Groningen, The Netherlands.

The EMBO Journal
|February 10, 2025
PubMed

Insights

Targeting drug-resistant breast cancer, this study reveals that cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) increase lysosomal mass. This makes cancer cells vulnerable to lysosomotropic agents, offering a novel sequential therapy approach.

Area of Science:

  • Oncology
  • Cell Biology
  • Drug Discovery

Background:

  • Breast cancer is a major global health concern, with cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) used to slow tumor growth by inducing senescence.
  • Drug resistance limits the long-term effectiveness of CDK4/6i, necessitating strategies to eliminate senescent cancer cells.

Purpose of the Study:

  • To investigate novel therapeutic vulnerabilities in CDK4/6i-treated breast cancer cells.
  • To identify agents capable of clearing CDK4/6i-induced senescent-like cells to improve treatment durability.

Main Methods:

  • Analysis of senescence-associated phenotypes in CDK4/6i-treated breast cancer cells.
  • Assessment of lysosomal mass and structure alterations following CDK4/6i exposure.
  • Testing the efficacy of lysosomotropic agents (LLOMe, salinomycin) in combination with CDK4/6i in preclinical models.

Main Results:

  • CDK4/6i-treated breast cancer cells, while senescent-like, are resistant to conventional senolytics.
  • CDK4/6i treatment significantly increases lysosomal mass and alters lysosomal structure in breast cancer cells.
  • Sequential treatment with CDK4/6i and lysosomotropic agents effectively inhibits tumor growth in both HR+ and some TNBC models in vivo.

Conclusions:

  • CDK4/6i induces lysosomal vulnerabilities in breast cancer cells, sensitizing them to lysosomotropic agents.
  • A sequential therapeutic strategy combining CDK4/6i with lysosomotropic agents shows promise for overcoming drug resistance and reducing recurrence.
  • This approach may enhance the overall efficacy of breast cancer therapy by targeting senescent-like cells.
Keywords:
AbemaciclibCDK4/6 InhibitorsCellular SenescenceLysosomep16

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