Imperial College London
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ProfessorIainMcNeish

Faculty of Medicine, Department of Surgery & Cancer

Chair in Oncology
 
 
 
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Contact

 

+44 (0)20 7594 2185i.mcneish Website

 
 
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Assistant

 

Ms Sophie Lions +44 (0)20 7594 2792

 
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Location

 

G036Institute of Reproductive and Developmental BiologyHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{McNeish:2020:10.15252/emmm.201911217,
author = {McNeish, I},
doi = {10.15252/emmm.201911217},
journal = {EMBO Molecular Medicine},
pages = {1--23},
title = {Tumors defective in homologous recombination rely on oxidative metabolism: Relevance to treatments with PARP inhibitors},
url = {http://dx.doi.org/10.15252/emmm.201911217},
volume = {12},
year = {2020}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - Mitochondrial metabolism and the generation of reactive oxygen species (ROS) contribute to the acquisition of DNA mutations and genomic instability in cancer. How genomic instability influences the metabolic capacity of cancer cells is nevertheless poorly understood. Here, we show that homologous recombinationdefective (HRD) cancers rely on oxidative metabolism to supply NAD+ and ATP for poly(ADPribose) polymerase (PARP)dependent DNA repair mechanisms. Studies in breast and ovarian cancer HRD models depict a metabolic shift that includes enhanced expression of the oxidative phosphorylation (OXPHOS) pathway and its key components and a decline in the glycolytic Warburg phenotype. Hence, HRD cells are more sensitive to metformin and NAD+ concentration changes. On the other hand, shifting from an OXPHOS to a highly glycolytic metabolism interferes with the sensitivity to PARP inhibitors (PARPi) in these HRD cells. This feature is associated with a weak response to PARP inhibition in patientderived xenografts, emerging as a new mechanism to determine PARPi sensitivity. This study shows a mechanistic link between two major cancer hallmarks, which in turn suggests novel possibilities for specifically treating HRD cancers with OXPHOS inhibitors.
AU  - McNeish,I
DO  - 10.15252/emmm.201911217
EP  - 23
PY  - 2020///
SN  - 1757-4676
SP  - 1
TI  - Tumors defective in homologous recombination rely on oxidative metabolism: Relevance to treatments with PARP inhibitors
T2  - EMBO Molecular Medicine
UR  - http://dx.doi.org/10.15252/emmm.201911217
UR  - https://www.embopress.org/doi/full/10.15252/emmm.201911217
UR  - http://hdl.handle.net/10044/1/79135
VL  - 12
ER  -
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