Integrated Pharmacodynamic Analysis Identifies Two Metabolic Adaption Pathways to Metformin in Breast Cancer.
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Authors
Lord, Simon R
Cheng, Wei-Chen
Liu, Dan
Gaude, Edoardo
Haider, Syed
Metcalf, Tom
Patel, Neel
Teoh, Eugene J
Gleeson, Fergus
Bradley, Kevin
Wigfield, Simon
Zois, Christos
McGowan, Daniel R
Ah-See, Mei-Lin
Thompson, Alastair M
Sharma, Anand
Bidaut, Luc
Pollak, Michael
Roy, Pankaj G
Karpe, Fredrik
James, Tim
English, Ruth
Adams, Rosie F
Campo, Leticia
Ayers, Lisa
Snell, Cameron
Roxanis, Ioannis
Fenwick, John D
Buffa, Francesca M
Harris, Adrian L
Publication Date
2018-11-06Journal Title
Cell Metab
ISSN
1550-4131
Publisher
Elsevier BV
Volume
28
Issue
5
Pages
679-688.e4
Language
eng
Type
Article
Physical Medium
Print-Electronic
Metadata
Show full item recordCitation
Lord, S. R., Cheng, W., Liu, D., Gaude, E., Haider, S., Metcalf, T., Patel, N., et al. (2018). Integrated Pharmacodynamic Analysis Identifies Two Metabolic Adaption Pathways to Metformin in Breast Cancer.. Cell Metab, 28 (5), 679-688.e4. https://doi.org/10.1016/j.cmet.2018.08.021
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.
Keywords
Mitochondria, Humans, Breast Neoplasms, Metformin, Glucose, Antineoplastic Agents, Hypoglycemic Agents, Gene Expression Regulation, Neoplastic, Adult, Aged, Middle Aged, Female, Metabolic Networks and Pathways, Transcriptome, Positron Emission Tomography Computed Tomography
Sponsorship
MRC (unknown)
Medical Research Council (MC_UU_12022/6)
Identifiers
External DOI: https://doi.org/10.1016/j.cmet.2018.08.021
This record's URL: https://www.repository.cam.ac.uk/handle/1810/285637
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