Pre-treatment with the CDK4/6 inhibitor palbociclib improves the efficacy of paclitaxel in TNBC cells

Daniele Cretella,Silvia La Monica,Claudia Fumarola,Mara Bonelli,Daniele Generali,Andrea Cavazzoni,Maricla Galetti,Graziana Digiacomo,Roberta Alfieri,Pier Giorgio Petronini

doi:10.1038/s41598-019-49484-4

Abstract

Triple Negative Breast Cancer (TNBC) is a challenging disease due to the lack of druggable targets; therefore, chemotherapy remains the standard of care and the identification of new targets is a high clinical priority. Alterations in the components of the cell cycle machinery have been frequently reported in cancer; given the success obtained with the CDK4/6 inhibitor palbocicib in ER-positive BC, we explored the potential of combining this drug with chemotherapy in Rb-positive TNBC cell models. The simultaneous combination of palbociclib with paclitaxel exerted an antagonistic effect; by contrast, the sequential treatment inhibited cell proliferation and increased cell death more efficaciously than single treatments. By down-regulating the E2F target c-myc, palbociclib reduced HIF-1α and GLUT-1 expression, and hence glucose uptake and consumption both under normoxic and hypoxic conditions. Importantly, these inhibitory effects on glucose metabolism were enhanced by palbociclib/paclitaxel sequential combination; the superior efficacy of such combination was ascribed to the ability of paclitaxel to inhibit palbociclib-mediated induction of AKT and to further down-regulate the Rb/E2F/c-myc signaling. Our results suggest that the efficacy of standard chemotherapy can be significantly improved by a pre-treatment with palbociclib, thus offering a better therapeutic option for Rb-proficient TNBC.

Highlights

Dysregulation of the cell cycle is a hallmark of cancer that leads to aberrant cellular proliferation with the consequent increase of genome instability
We provide evidence that the sequential treatment of palbociclib followed by paclitaxel is effective in Triple negative breast cancer (TNBC) cell lines, producing additive anti-proliferative and pro-apoptotic effects associated with impairment of glucose metabolism
We previously showed that palbociclib inhibited cell proliferation in TNBC cell lines characterized by retinoblastoma protein (Rb), cyclin D1, and CDK6 protein expression, along with p16INK4 loss[13]

Summary

Introduction

Dysregulation of the cell cycle is a hallmark of cancer that leads to aberrant cellular proliferation with the consequent increase of genome instability. The inhibition of cell cycle regulators such as CDK4 and CDK6 has become a new therapeutic frontier for the treatment of breast cancer (BC). The expression of proteins involved in the control of cell cycle progression, such as cyclin D1, and the loss of the cell cycle inhibitor p16INK4a have been associated with a better response to CDK4/6 inhibitors in BC cells[3,4]. Triple negative breast cancer (TNBC) lacks the expression of ER, progesterone receptor (PR) and HER-2. This subtype accounts for approximately 15–20% of BC5 and is characterized by the poorest prognosis in respect to other BC malignancies. The timing and the sequence of drug exposure might play a critical role in drug activity, and the evaluation of different schedules of treatment may represent a new approach for the combination of palbociclib with chemotherapy

Methods

Results

Conclusion