Integrated Pharmacodynamic Analysis Identifies Two Metabolic Adaption Pathways to Metformin in Breast Cancer

Simon R. Lord (Lead / Corresponding author), Wei-Chen Cheng, Dan Liu, Edoardo Gaude, Syed Haider, Tom Metcalf, Neel Patel, Eugene J. Teoh, Fergus Gleeson, Kevin Bradley, Simon Wigfield, Christos Zois, Daniel R. McGowan, Mei-Lin Ah-See, Alastair M. Thompson, Anand Sharma, Luc Bidaut, Michael Pollak, Pankaj G. Roy, Fredrik KarpeTim James, Ruth English, Rosie F. Adams, Leticia Campo, Lisa Ayers, Cameron Snell, Ioannis Roxanis, Christian Frezza, John D. Fenwick, Francesca M. Buffa, Adrian L. Harris

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Abstract

Late-phase clinical trials investigating metformin as a cancer therapy are underway. However, there remains controversy as to the mode of action of metformin in tumors at clinical doses. We conducted a clinical study integrating measurement of markers of systemic metabolism, dynamic FDG-PET-CT, transcriptomics, and metabolomics at paired time points to profile the bioactivity of metformin in primary breast cancer. We show metformin reduces the levels of mitochondrial metabolites, activates multiple mitochondrial metabolic pathways, and increases 18-FDG flux in tumors. Two tumor groups are identified with distinct metabolic responses, an OXPHOS transcriptional response (OTR) group for which there is an increase in OXPHOS gene transcription and an FDG response group with increased 18-FDG uptake. Increase in proliferation, as measured by a validated proliferation signature, suggested that patients in the OTR group were resistant to metformin treatment. We conclude that mitochondrial response to metformin in primary breast cancer may define anti-tumor effect.

Original languageEnglish
Pages (from-to)679-688.e4
Number of pages15
JournalCell Metabolism
Volume28
Issue number5
Early online date20 Sep 2018
DOIs
Publication statusPublished - 6 Nov 2018

Keywords

  • breast neoplasms
  • cancer metabolism
  • clinical study
  • gene expression profiling
  • metabolomics
  • metformin
  • mitochondria
  • positron emission tomography

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    Lord, S. R., Cheng, W-C., Liu, D., Gaude, E., Haider, S., Metcalf, T., Patel, N., Teoh, E. J., Gleeson, F., Bradley, K., Wigfield, S., Zois, C., McGowan, D. R., Ah-See, M-L., Thompson, A. M., Sharma, A., Bidaut, L., Pollak, M., Roy, P. G., ... Harris, A. L. (2018). Integrated Pharmacodynamic Analysis Identifies Two Metabolic Adaption Pathways to Metformin in Breast Cancer. Cell Metabolism, 28(5), 679-688.e4. https://doi.org/10.1016/j.cmet.2018.08.021