Pharmacological CDK4/6 inhibition reveals a p53‐dependent senescent state with restricted toxicity

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.

Cells on lockdown: long‐term consequences of CDK4/6 inhibition

“…The study by Crozier et al (2022) highlights a source of heterogeneity in the induction of senescence/long‐term arrest in cells after CDK4/6i washout—with cells arrested in either a G0/G1‐ or a G2‐like state. This has implications for the secretome phenotype identified by Wang et al (2022). Do both G0/G1‐ and G2‐arrested populations secrete the same factors?…”

“…The Saurin and Demaria groups set out with differing initial goals: Crozier et al (2022) focussed on identifying the mechanisms by which treatment with Cdk4/6 inhibitors (Cdk4/6i) promoted entry into senescence, while Wang et al (2022) aimed to characterise the downstream impact of senescence induction by Cdk4/6i. Both laboratories found that treating non‐cancer cells for a prolonged period of time (i.e.…”

“…However, how p53 is activated during a G0/G1 arrest, in the presence of Cdk4/6i, and how p53 is maintained after inhibitor washout, remains unknown. Increased levels of mitochondrial reactive oxygen species (ROS) in cells treated with Cdk4/6i may help to promote p53 activation, although this does not involve ROS‐mediated DNA damage (Wang et al, 2022). Determining the source of p53 activation would allow us to intelligently predict Cdk4/6i combination therapies to ensure that this particular p53 response is not diminished.…”

“…Seeking to understand how the toxicity of Cdk4/6i is limited to cancer cells, Wang et al (2022) used in vivo experiments in mice to determine whether Cdk4/6i leads to senescence in non‐transformed cells. They treated cancer‐free mice with either Cdk4/6i or doxorubicin—a common DNA damage‐inducing chemotherapeutic—at doses normally capable of reducing tumour volume.…”

“…These studies were performed in cancer‐free mice, and it would be interesting to see how this compared to mice with tumours. To understand the mechanism for these differences in toxicity, Wang et al (2022) looked into the composition of the senescence‐associated secretory phenotype (SASP), a well‐characterised set of factors secreted by senescent cells. DNA damage responses induced by doxorubicin lead to the activation of a key signalling nexus, NF‐ϰB, which promotes a pro‐inflammatory SASP.…”