Background: CDK4/6 inhibitors (CDKi) have improved disease control in hormone-receptor-positive, HER2-negative metastatic breast cancer, but most patients develop progressive disease. Methods: We asked whether host stromal senescence after CDK4/6 inhibition affects metastatic seeding and growth of CDKi-resistant mammary cancer cells by using the p16-INK-ATTAC mouse model of inducible senolysis. Results: Palbociclib pretreatment of naïve mice increased lung seeding of CDKi-resistant syngeneic mammary cancer cells, and this effect was reversed by depletion of host senescent cells. RNA sequencing analyses of lungs from non-tumor-bearing p16-INK-ATTAC mice identified that palbociclib downregulates immune-related gene sets and gene expression related to leukocyte migration. Concomitant senolysis reversed a portion of these effects, including pathway-level enrichment of TGF-β- and senescence-related signaling. CIBERSORTx analysis revealed that palbociclib alters intra-lung macrophage/monocyte populations. Notably, lung metastases from palbociclib-pretreated mice revealed senescent endothelial cells. Palbociclib-treated endothelial cells exhibit hallmark senescent features in vitro, upregulate genes involved with the senescence-associated secretory phenotype, leukocyte migration, and TGF-β-mediated paracrine senescence and induce tumor cell migration and monocyte trans-endothelial invasion in co-culture. Conclusions: These studies shed light on how stromal senescence induced by palbociclib affects lung metastasis, and they describe palbociclib-induced gene expression changes in the normal lung and endothelial cell models that correlate with changes in the tumor microenvironment in the lung metastatic niche.

Physiologic aging and insults from the environment lead to DNA damage. In response, cells in any organ will undergo senescence-induced growth arrest to prevent damaged cells from further propagation. This review focuses on senescence pharmacology. First, we describe senescence induction mechanisms and a unique feature of senescent cells, the SASP (senescence-associated secretory phenotype). Signaling pathways that control and respond to the SASP provide the framework for a better understanding of senescence pharmacology. We describe how several commonly used drugs can induce cellular senescence and how that impacts their efficacy and produces unexpected effects. Thereafter, we discuss the potential and challenges of senolytic drugs that eliminate senescent cells, and we describe targeting of components of the SASP as well as pathways that control expression of genes contributing to the SASP. Lastly, we discuss studies that have exemplified the significant impact of senescence-targeted therapy in various disease states.