Pharmacological CDK4/6 inhibition reveals a p53-dependent senescent state with restricted toxicity
Boshi Wang1, Marta Varela-Eirin1, Simone M Brandenburg1
1European Research Institute for the Biology of Ageing (ERIBA), University Medical Center Groningen (UMCG), Groningen, The Netherlands.
Abstract:
Cellular senescence is a state of stable growth arrest and a desired outcome of tumor suppressive interventions. Treatment with many anti-cancer drugs can cause premature senescence of non-malignant cells. These therapy-induced senescent cells can have pro-tumorigenic and pro-disease functions via activation of an inflammatory secretory phenotype (SASP). Inhibitors of cyclin-dependent kinases 4/6 (CDK4/6i) have recently proven to restrain tumor growth by activating a senescence-like program in cancer cells. However, the physiological consequence of exposing the whole organism to pharmacological CDK4/6i remains poorly characterized. Here, we show that exposure to CDK4/6i induces non-malignant cells to enter a premature state of senescence dependent on p53. We observe in mice and breast cancer patients that the CDK4/6i-induced senescent program activates only a partial SASP enriched in p53 targets but lacking pro-inflammatory and NF-κB-driven components. We find that CDK4/6i-induced senescent cells do not acquire pro-tumorigenic and detrimental properties but retain the ability to promote paracrine senescence and undergo clearance. Our results demonstrate that SASP composition is exquisitely stress-dependent and a predictor for the biological functions of different senescence subsets.
Insights
Pharmacological CDK4/6 inhibitors induce p53-dependent senescence in non-malignant cells. These cells exhibit a partial SASP, lacking pro-tumorigenic traits, and promote clearance, unlike other senescent cells.
Area of Science:
- Cellular biology
- Oncology
- Aging research
Background:
- Cellular senescence is a tumor-suppressive mechanism, but therapy-induced senescence can promote disease.
- Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) induce senescence in cancer cells.
- The systemic effects of CDK4/6i on non-malignant cells are not well understood.
Purpose of the Study:
- To investigate the impact of pharmacological CDK4/6 inhibitors on non-malignant cells.
- To characterize the senescence-associated secretory phenotype (SASP) induced by CDK4/6i.
- To determine the functional consequences of CDK4/6i-induced senescence.
Main Methods:
- Treatment of mice and human cells with CDK4/6 inhibitors.
- Analysis of senescence markers and p53 dependency.
- Characterization of the SASP composition using molecular assays.
- Assessment of pro-tumorigenic and clearance properties of senescent cells.
Main Results:
- CDK4/6i induces p53-dependent premature senescence in non-malignant cells.
- CDK4/6i-induced senescence activates a partial SASP, enriched in p53 targets but lacking pro-inflammatory factors.
- These senescent cells do not exhibit pro-tumorigenic functions and retain the capacity for clearance.
Conclusions:
- SASP composition is highly dependent on the inducing stress.
- CDK4/6i-induced senescence in non-malignant cells is not detrimental and may promote organismal health.
- Understanding SASP heterogeneity is crucial for predicting senescence functions.
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