title: Decreased glutathione biosynthesis contributes to EGFR T790M-driven erlotinib resistance in non-small cell lung cancer.
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.
authors.affiliation: State Key Laboratory of Genetic Engineering, Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Centre for Genetics and Development, Shanghai International Centre for Molecular Phenomics, Metabonomics and Systems Biology Laboratory, Department of Biochemistry, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai, China; Key Laboratory of Magnetic Resonance in Biological Systems, National Centre for Magnetic Resonance in Wuhan, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences, Wuhan, China.
authors.forename: Hongde
authors.initials: H
authors.lastname: Li
authors.affiliation: Division of Cancer, Department of Surgery and Cancer, Imperial College, Hammersmith Hospital , London, UK.
authors.forename: William
authors.initials: W
authors.lastname: Stokes
authors.affiliation: Division of Cancer, Department of Surgery and Cancer, Imperial College, Hammersmith Hospital , London, UK.
authors.forename: Emily
authors.initials: E
authors.lastname: Chater
authors.affiliation: Division of Cancer, Department of Surgery and Cancer, Imperial College, Hammersmith Hospital , London, UK.
authors.forename: Rajat
authors.initials: R
authors.lastname: Roy
authors.affiliation: Signal Transduction Laboratory, CRUK London Research Institute, London, UK; Personalised Healthcare & Biomarkers, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Cambridge, UK.
authors.forename: Elza
authors.initials: E
authors.lastname: de Bruin
authors.affiliation: Key Laboratory of Magnetic Resonance in Biological Systems, National Centre for Magnetic Resonance in Wuhan, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences , Wuhan, China.
authors.forename: Yili
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Key Laboratory of Magnetic Resonance in Biological Systems, National Centre for Magnetic Resonance in Wuhan, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences , Wuhan, China.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Pulmonary Diseases, VU University Medical Centre, Netherlands Cancer Institute , Amsterdam, Netherlands.
authors.forename: Egbert F
authors.initials: EF
authors.lastname: Smit
authors.affiliation: Section of Molecular Carcinogenesis, Netherlands Cancer Institute , Amsterdam, Netherlands.
authors.forename: Guus Jje
authors.initials: GJ
authors.lastname: Heynen
authors.affiliation: Signal Transduction Laboratory, CRUK London Research Institute , London, UK.
authors.forename: Julian
authors.initials: J
authors.lastname: Downward
authors.affiliation: Division of Cancer, Department of Surgery and Cancer, Imperial College, Hammersmith Hospital , London, UK.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Seckl
authors.affiliation: Key Laboratory of Magnetic Resonance in Biological Systems, National Centre for Magnetic Resonance in Wuhan, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences, Wuhan, China; Collaborative Innovation Centre for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China.
authors.forename: Yulan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Genetic Engineering, Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Centre for Genetics and Development, Shanghai International Centre for Molecular Phenomics, Metabonomics and Systems Biology Laboratory, Department of Biochemistry, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai, China; Key Laboratory of Magnetic Resonance in Biological Systems, National Centre for Magnetic Resonance in Wuhan, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences, Wuhan, China.
authors.forename: Huiru
authors.initials: H
authors.lastname: Tang
authors.affiliation: Division of Cancer, Department of Surgery and Cancer, Imperial College, Hammersmith Hospital , London, UK.
authors.forename: Olivier E
authors.initials: OE
authors.lastname: Pardo
keywords: TKI; drug resistance; glutathione; lung cancer; metabolomics