Imperial College London


Faculty of MedicineDepartment of Surgery & Cancer




+44 (0)20 3313 3759eric.aboagye




Mrs Maureen Francis +44 (0)20 7594 2793




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BibTex format

author = {Li, H and Stokes, WB and Chater, E and Rupniewska, E and Roy, R and Mauri, FA and Liu, X and Kaliszczak, M and Downward, J and Aboagye, E and Tang, H and Wang, Y and Seckl, MJ and Pardo, OE},
doi = {10.1016/j.mgene.2018.05.044},
journal = {Meta Gene},
title = {Resistance to tyrosine kinase-targeted therapy in lung cancer: Autophagy and metabolic changes},
url = {},
year = {2018}

RIS format (EndNote, RefMan)

AB - © 2018 Lung cancer is the commonest cancer killer worldwide. Tyrosine-kinase inhibitors (TKI) are novel agents in the treatment of this cancer. However, their efficacy is impaired by the rapid development of drug-resistance through a variety of mechanisms. Here, we will discuss resistance to the first-generation EGFR inhibitors (e.g. Erlotinib) and SRC inhibitors (e.g. Dasatinib). The principal mechanism of resistance to first-generation EGFR inhibitors is the appearance of the T790M receptor mutation. While the reason for resistance was proposed to be changes in affinity of the receptor for ATP, our metabolomics analysis additionally revealed that resistance is associated with decreased cellular levels of glutathione (GSH), a direct consequence of the T790M mutation. This occurred because of decreased SQSTM1/NRF2-mediated transcription of GSH synthesising enzymes in cell lines and clinical samples with T790M-EGFR. We demonstrate that increasing GSH levels in resistant cells re-sensitises these to first-generation EGFR inhibitors in vitro and in vivo. As compounds exist in the clinic to achieve this, our finding may have profound therapeutic and economic consequences. Src family kinases (SFK) are commonly overexpressed or hyperactivated in lung cancer cell lines and clinical samples. However, despite their on-target efficacy, SRC inhibitors have failed to prevent tumour growth and improve patients’ survival in multiple clinical trial. Here we show that this failure is associated with the induction of autophagy in treated cells that prevents these compounds from triggering apoptosis cell death. Targeting autophagy, either genetically or using our novel small-molecule inhibitor, C1A, sensitises lung cancer cell lines to Dasatinib both in vitro and in vivo by unlocking the apoptotic response. These findings propose new combinational therapeutic strategies that could resurrect the use of SRC inhibitors in the treatment of lung cancer.
AU - Li,H
AU - Stokes,WB
AU - Chater,E
AU - Rupniewska,E
AU - Roy,R
AU - Mauri,FA
AU - Liu,X
AU - Kaliszczak,M
AU - Downward,J
AU - Aboagye,E
AU - Tang,H
AU - Wang,Y
AU - Seckl,MJ
AU - Pardo,OE
DO - 10.1016/j.mgene.2018.05.044
PY - 2018///
TI - Resistance to tyrosine kinase-targeted therapy in lung cancer: Autophagy and metabolic changes
T2 - Meta Gene
UR -
ER -