Olivier E Pardo
Imperial College London, UK
Title: Resistance to tyrosine kinase-targeted therapy in lung cancer: Autophagy and metabolic changes
Biography
Biography: Olivier E Pardo
Abstract
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. Here, we discuss resistance to the first-generation EGFR inhibitors (eg. Erlotinib and SRC inhibitors eg. Dasatinib). The principal mechanism of resistance to first-generation EGFR inhibitors is the appearance of the T790M receptor mutation. Our metabolomics analysis 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 synthesizing enzymes in cell lines and clinical samples with T790M-EGFR. Increasing GSH levels in resistant cells re-sensitizes these to first-generation EGFR inhibitors in vitro and in vivo. As clinically-relevant compounds exist to achieve this, our finding may have profound therapeutic and economic consequences. Src family kinases (SFK) are commonly over-expressed/hyperactivated in lung cancer. However, despite their on-target efficacy, SRC inhibitors have failed to prevent tumour growth and improve patients’ survival in multiple clinical trials. Here we show that this failure is associated with the induction of autophagy in treated cells that prevents these compounds from triggering apoptosis. Targeting autophagy, either genetically or using our novel small-molecule inhibitor, C1A, sensitizes 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.