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.