Integrated pharmacodynamic analysis identifies two metabolic adaption pathways to metformin in breast cancer


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Simon Lord1,Wei-Chen Cheng1,Dan Liu1,Edoardo Guade2,Syed Haider3,Tom Metcalf4,Neel Patel1,Fergus Gleeson1,Alastair Thompson5,Michael Pollak6,Roy Pankaj7,Christian Frezza8,John Fenwick4,Franceca Buffa1,Adrian Harris1
1University of Oxford,2University of Cambridge,3Institute of Cancer Research,4University of Liverpool,5MD Anderson Cancer Centre,6McGill University,7Oxford University Hospitals NHS Foundation Trust,8University of Cambridage

Abstract

Background

Epidemiological studies have shown that treatment of type 2 diabetes with metformin is associated with reduced cancer risk and phase 3 trials investigating metformin as a cancer therapy are underway. However, there remains controversy as to the mode of action of metformin in tumours at clinical doses.

Method

To investigate this we recruited 40 patients with primary breast cancer to a clinical study that integrated measurement of markers of systemic metabolism, dynamic FDG-PET-CT and tumour transcriptomics and metabolomics at paired time points to profile the bioactivity of metformin.

Results

We show metformin reduces the levels of mitochondrial metabolites in tumours, activates multiple mitochondrial metabolic pathways and increases 18-FDG flux into the primary tumour. We identify two tumour groups with distinct metabolic responses, an OXPHOS transcriptional response group (OTR) for which there is an increase in OXPHOS gene transcription and an FDG response group (FR) with increased 18-FDG uptake. Increase in proliferation, as measured by a validated proliferation signature, suggested patients in the OTR group were resistant to metformin treatment. There was no observed correlation between metformin’s effects on host metabolism and its tumour specific effects.

Conclusion

We conclude that mitochondrial response to metformin in primary breast cancer may define anti-tumour effect.