Palbociclib and fulvestrant act in synergy to modulate central carbon metabolism in breast cancer cells

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

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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.

Original languageEnglish
Article number7
Number of pages15
JournalMetabolites
Volume9
Issue number1
DOIs
Publication statusPublished - 2 Jan 2019

Keywords

  • breast cancer
  • combination drug therapy
  • metabolomics
  • multi-omics
  • RNA-seq
  • XCMS online

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