CDK4/6 Inhibition Promotes a P53-Dependent Senescent State with Restricted Secretory Phenotype

Abstract

Cellular senescence is a state of stable growth arrest that acts as a tumor suppressive mechanism and desired outcome of anti-cancer interventions. Because of systemic administration and lack of tumor specificity, treatment with many anti-cancer drugs can cause premature senescence of non-malignant cells. These therapy-induced senescent cells can have profound detrimental pro-tumorigenic and pro-disease functions via activation of a pro-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, but their effect on normal cells, particularly in vivo, remains poorly characterized. Here, we observe that, in culture and in mice, exposure to CDK4/6i leads normal cells into a p53-dependent state of premature senescence. We demonstrate that the CDK4/6i-induced senescent program engages a SASP enriched in direct p53 targets (PASP) but without a pro-inflammatory and NF-κB-associated secretory phenotype (NASP). We show that tumor suppressive doses of CDK4/6i cause a PASP but not a NASP in tissues and plasma from mice and breast cancer patients. We also show that because lacking a NASP, CDK4/6i-induced senescent cells do not acquire pro-tumorigenic properties, and do not promote severe adverse reactions, in particular asthenia, in vivo. Our data suggest that senescent cells with a PASP but without a NASP maintain beneficial properties for cancer therapy without developing detrimental functions, thus representing a potentially less toxic and better tolerated outcome for interventions.