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

    Research output: Contribution to journalArticlepeer-review

    98 Citations (Scopus)
    164 Downloads (Pure)

    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 Sept 2018
    DOIs
    Publication statusPublished - 6 Nov 2018

    Keywords

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

    ASJC Scopus subject areas

    • Physiology
    • Molecular Biology
    • Cell Biology

    Fingerprint

    Dive into the research topics of 'Integrated Pharmacodynamic Analysis Identifies Two Metabolic Adaption Pathways to Metformin in Breast Cancer'. Together they form a unique fingerprint.

    Cite this