Imperial College London
Alternate

ProfessorMichaelSeckl

Faculty of Medicine, Department of Surgery & Cancer

Professor of Molecular Cancer Medicine
 
 
 
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Contact

 

+44 (0)20 3311 1421m.seckl

 
 
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Location

 

08Cyclotron buildingHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Li:2016:10.1038/celldisc.2016.31,
author = {Li, H and Stokes, W and Chater, E and Roy, R and de, Bruin E and Hu, Y and Liu, Z and Smit, EF and Heynen, GJJE and Downward, J and Seckl, MJS and Wang, Y and Tang, H and Pardo, OE},
doi = {10.1038/celldisc.2016.31},
journal = {Cell Discovery},
title = {Decreased glutathione biosynthesis contributes to EGFR T790M-driven erlotinib resistance in non-small cell lung cancer},
url = {http://dx.doi.org/10.1038/celldisc.2016.31},
volume = {2},
year = {2016}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - Epidermal growth factor receptor (EGFR) inhibitors such as erlotinib are novel effective agents in the treatment of EGFR-driven lung cancer, but their clinical impact is often impaired by acquired drug resistance through the secondary T790M EGFR mutation. To overcome this problem, we analysed the metabonomic differences between two independent pairs of erlotinib-sensitive/resistant cells and discovered that glutathione (GSH) levels were significantly reduced in T790M EGFR cells. We also found that increasing GSH levels in erlotinib-resistant cells re-sensitised them, whereas reducing GSH levels in erlotinib-sensitive cells made them resistant. Decreased transcription of the GSH-synthesising enzymes (GCLC and GSS) due to the inhibition of NRF2 was responsible for low GSH levels in resistant cells that was directly linked to the T790M mutation. T790M EGFR clinical samples also showed decreased expression of these key enzymes; increasing intra-tumoural GSH levels with a small-molecule GST inhibitor re-sensitised resistant tumours to erlotinib in mice. Thus, we identified a new resistance pathway controlled by EGFR T790M and a therapeutic strategy to tackle this problem in the clinic.
AU  - Li,H
AU  - Stokes,W
AU  - Chater,E
AU  - Roy,R
AU  - de,Bruin E
AU  - Hu,Y
AU  - Liu,Z
AU  - Smit,EF
AU  - Heynen,GJJE
AU  - Downward,J
AU  - Seckl,MJS
AU  - Wang,Y
AU  - Tang,H
AU  - Pardo,OE
DO  - 10.1038/celldisc.2016.31
PY  - 2016///
SN  - 2056-5968
TI  - Decreased glutathione biosynthesis contributes to EGFR T790M-driven erlotinib resistance in non-small cell lung cancer
T2  - Cell Discovery
UR  - http://dx.doi.org/10.1038/celldisc.2016.31
UR  - http://hdl.handle.net/10044/1/38494
VL  - 2
ER  -
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