Oncotarget

Research Papers:

Combining AKT inhibition with chloroquine and gefitinib prevents compensatory autophagy and induces cell death in EGFR mutated NSCLC cells

Sivan M. Bokobza, Yanyan Jiang, Anika M. Weber, Aoife M. Devery and Anderson J. Ryan _

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Oncotarget. 2014; 5:4765-4778. https://doi.org/10.18632/oncotarget.2017

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Abstract

Sivan M. Bokobza1, Yanyan Jiang1, Anika M. Weber1, Aoife M. Devery1 and Anderson J. Ryan1

1 Gray Institute for Radiation Oncology & Biology, Department of Oncology, University of Oxford, Old Road Campus Research Building, Headington, Oxford, UK

Correspondence:

Anderson J Ryan, email:

Keywords: EGFR, lung cancer, AKT, Chloroquine

Received: March 20, 2014 Accepted: May 25, 2014 Published: May 27, 2014

Abstract

Although non-small cell lung cancer (NSCLC) patients with EGFR mutation positive (EGFR M+) tumors initially respond well to EGFR tyrosine kinase inhibitor (TKI) monotherapy, the responses are usually incomplete. In this study we show that AKT inhibition, most importantly AKT2 inhibition, synergises with EGFR TKI inhibition to increase cell killing in EGFR M+ NSCLC cells. However, our data also suggest that the synergistic pro-apoptotic effects may be stunted due to a prosurvival autophagy response induced by AKT inhibition. Consequently, inhibiting autophagy with chloroquine significantly enhanced tumor cell death induced by gefitinib and AKT inhibitors in EGFR M+ cells in vitro, and produced greater tumor shrinkage in EGFR M+ xenografts in vivo. Together, our findings suggest that adding chloroquine to EGFR and AKT inhibition has the potential to improve tumor responses in EGFR M+ NSCLC, and that selective targeting of AKT2 may provide a new treatment option in NSCLC.


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