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Decreased glutathione biosynthesis contributes to EGFR T790M-driven erlotinib resistance in non-small cell lung cancer

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Title: Decreased glutathione biosynthesis contributes to EGFR T790M-driven erlotinib resistance in non-small cell lung cancer
Authors: Li, H
Stokes, W
Chater, E
Roy, R
De Bruin, E
Hu, Y
Liu, Z
Smit, EF
Heynen, GJJE
Downward, J
Seckl, MJS
Wang, Y
Tang, H
Pardo, OE
Item Type: Journal Article
Abstract: 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.
Issue Date: 27-Sep-2016
Date of Acceptance: 14-Jul-2016
URI: http://hdl.handle.net/10044/1/38494
DOI: https://dx.doi.org/10.1038/celldisc.2016.31
ISSN: 2056-5968
Publisher: Nature Publishing Group
Journal / Book Title: Cell Discovery
Volume: 2
Copyright Statement: This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ © The Author(s) 2016
Sponsor/Funder: Commission of the European Communities
Cancer Treatment & Research Trust
Cancer Research UK
Cancer Treatment & Research Trust
National Institute for Health Research
Worldwide Cancer Research
Imperial College Healthcare NHS Trust- BRC Funding
Cancer Treatment & Research Trust
Funder's Grant Number: 259770
n/a
C1312/A15589
N/A
RDEMC 79560
13-0318
RDB01 79560
N/A
Publication Status: Published
Article Number: 16031
Appears in Collections:Division of Surgery
Division of Cancer
Faculty of Medicine



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