Stromal Senescence following Treatment with the CDK4/6 Inhibitor Palbociclib Alters the Lung Metastatic Niche and Increases Metastasis of Drug-Resistant Mammary Cancer Cells

Abstract

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.

Ratios of monocytes and neutrophils to lymphocytes in the blood predict benefit of CDK4/6 inhibitor treatment in metastatic breast cancer

“…In a mouse model representing lung metastases in the BC setting, it was shown that circulating monocyctes were reduced in number under CDK4/6i, but an increase in monocyte invasion was detected 40 . The decrease in circulating monocyte number was detected in CDK4/6i patients in our project as well.…”

The Evolving Pathways of the Efficacy of and Resistance to CDK4/6 Inhibitors in Breast Cancer

“…Multiple preclinical studies reported that CDK4/6i can induce a senescence-like state in cancer cells characterized by cellular enlargement and increased senescence-associated β-galactosidase (SAβGal) activity [83][84][85][86][87][88][89]. Two studies showed that this senescent-like state seems to be mostly Rb-dependent [90,91], which is not surprising since Rb is one of the key mediators of cellular senescence, as recently reviewed [92], but might also be linked to reduced activity of the direct CDK4/6 substrates forkhead box protein M1 (FOXM1) [93,94] and DNA methyltransferase 1 (DNMT1) [94].…”

CDKN1A/p21 in Breast Cancer: Part of the Problem, or Part of the Solution?

“…Initially recognised for its anti-tumoural attributes due to the permanent cessation of the cell cycle, recent findings have suggested a potential oncogenic role: senescence may facilitate cellular migration and metastasis [164,165]. Notably, senescence induced by anti-cancer treatments emerges as a pivotal factor influencing recurrence and metastatic events [166][167][168], and key drivers of senescence are targets for cancer therapy drug development pipelines.…”