Palbociclib and Fulvestrant Act in Synergy to Modulate Central Carbon Metabolism in Breast Cancer Cells.

Benedikt Warth,Valeria R Fantin,Nicholas J.W Rattray,Gary Siuzdak,Caroline H Johnson,Zhou Zhu,Linh T Hoang,Stephen Dann,Amelia Palermo,Todd Vanarsdale,Anthony Mazurek,Yuping Cai,Nathan V Lee,David Shields

doi:10.3390/metabo9010007

Abstract

The aims of this study were to determine whether combination chemotherapeutics exhibit a synergistic effect on breast cancer cell metabolism. Palbociclib, is a selective inhibitor of cyclin-dependent kinases 4 and 6, and when patients are treated in combination with fulvestrant, an estrogen receptor antagonist, they have improved progression-free survival. The mechanisms for this survival advantage are not known. Therefore, we analyzed metabolic and transcriptomic changes in MCF-7 cells following single and combination chemotherapy to determine whether selective metabolic pathways are targeted during these different modes of treatment. Individually, the drugs caused metabolic disruption to the same metabolic pathways, however fulvestrant additionally attenuated the pentose phosphate pathway and the production of important coenzymes. A comprehensive effect was observed when the drugs were applied together, confirming the combinatory therapy’s synergism in the cell model. This study also highlights the power of merging high-dimensional datasets to unravel mechanisms involved in cancer metabolism and therapy.

Highlights

Cell cycle regulation is frequently disrupted in breast cancer [1,2]
To identify metabolic pathways modulated by the drugs, MCF-7 breast cancer cells
The The results indicated that two days after a simultaneous dose of both drugs metabolites were dysregulated in multiple metabolic pathways in central carbon fulvestrant) metabolites were dysregulated in multiple metabolic pathways in central carbon metabolism: The tricarboxylic acid (TCA) cycle, phosphate pathway (PPP), and purine synthesis

Summary

Introduction

Cell cycle regulation is frequently disrupted in breast cancer [1,2]. Cyclin-dependent kinases (CDKs) control this regulation enabling quiescent cells to enter the G1 -phase and transition to theS phase. Cell cycle regulation is frequently disrupted in breast cancer [1,2]. Cyclin-dependent kinases (CDKs) control this regulation enabling quiescent cells to enter the G1 -phase and transition to the. CDKs 4 and 6 phosphorylate the retinoblastoma (RB) protein enabling the release of E2F transcription factors (E2Fs) which mediates transition into the S-phase. Mutations to the CDK-RB1-E2F pathway typically result in the amplification of CCND1 which encodes cyclin D1. Both are correlated with estrogen receptor positive (ER+) breast cancers.

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