Effects of CDK4/6 Inhibition on Progression of Early Stage Breast Cancer
Riegel, Anna T
Here we demonstrate the efficacy of palbociclib in targeting the cell cycle kinase CDK4/6 and canonical pathways downstream in both normal breast epithelial (MCF10A) and early stage breast cancer cells (MCFDCIS) resulting in inhibition of proliferation and a dose-dependent induction of senescence. Though these cell lines exhibit similar 2D sensitivity, in 3D palbociclib is selectively effective on MCFDCIS tumorspheres generating smaller more organized structures while MCF10A mammary acini are unaffected by treatment. In vivo we demonstrate that short term palbociclib slows triple negative and basal MCFDCIS tumor growth resulting in significantly smaller lesions and a delayed invasive transition, mediated primarily through the downregulation of proliferative targets in both the human tumor cells and the associated mouse stroma. This effect appears predominantly cytostatic as MCFDCIS tumors did not regress on treatment and are able to recover and reinitiate growth and progression upon treatment cessation. Despite the recovery of proliferative genes, some genes involved in pathways such as EMT, invasion and immunity remain downregulated after discontinuation of drug.We demonstrate the transcription factor, FOXM1 to be a bona fide CDK4/6 target. FOXM1 expression and activity is significantly diminished by palbociclib treatment, on plastic, in 3D culture and in MCFDCIS xenografts and we show that this regulation is important to drug induced senescence. Though FOXM1 mRNA levels recover after treatment cessation, protein levels do not, suggesting that FOXM1 may be valuable marker of palbociclib response but is not primarily responsible for its cytotstatic or senescent effects.Another potential marker identified is the glycoprotein MUC16. We demonstrate that MUC16 levels fall in response to palbociclib and knocking down MUC16 expression in MCFDCIS cells results in delayed tumor growth. This suggests some benefit to palbociclib may be mediated through MUC16 repression. MUC16 can be detected in the blood and it correlates with tumor expression meaning it could be used to test for on target responses to palbociclib in real time using blood samples.These results indicate on target efficacy of CDK4/6 inhibition in a basal and triple negative model of DCIS while also highlighting novel markers of drug response and recovery with potential clinical application.
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