CDK4/6 inhibition promotes senescent states with restricted secretory phenotype and reduced toxicity

Cellular senescence is a state of stable growth arrest that acts as a tumor suppressive mechanism. Genotoxic agents exert their anti-cancer functions partly by inducing cancer cells into senescence. However, because of systemic administration and lack of specificity, treatment with genotoxic agents is associated with premature senescence of various non-cancerous cells. Therapy-induced normal senescent cells can have profound detrimental pro-tumorigenic and pro-disease functions via activation of a pro-inflammatory secretory phenotype (SASP). Alternative to genotoxic agents, inhibitors of cyclin-dependent kinases 4/6 (CDK4/6i) have recently proven to be potent anti-cancer interventions able to activate a poorly characterized senescence-like state. Here, we demonstrate that establishment of CDK4/6i-induced stable growth arrest is dependent on p53 transcriptional activity. We show that in human cells, mouse tissues and plasma of metastatic breast cancer patients the CDK4/6i-induced senescent program engages only a partial SASP enriched in p53-associated genes (PASP) but without pro-inflammatory and detrimental NF-κB-dependent factors (NASP). Because of the lack of a NASP, CDK4/6i-induced p16 senescent cells do not exert detrimental and pro-tumorigenic functions in culture and . Interestingly, short-term treatment of chemotherapy-induced senescent cells with CDK4/6i is sufficient to partially reduce an already established NASP and improve mouse healthspan via p53 activation and NF-κB repression. Our data suggest that short- and long-term treatment with CDK4/6i can modulate senescence-associated phenotypes and restrict the detrimental effects of senescent cells in cancer therapy.