Abstract
Human lung adenocarcinomas with activating mutations in EGFR (epidermal growth factor receptor) often respond to treatment with EGFR tyrosine kinase inhibitors (TKIs), but the magnitude of tumour regression is variable and transient1,2. This heterogeneity in treatment response could result from genetic modifiers that regulate the degree to which tumour cells are dependent on mutant EGFR. Through a pooled RNA interference screen, we show that knockdown of FAS and several components of the NF-κB pathway specifically enhanced cell death induced by the EGFR TKI erlotinib in EGFR-mutant lung cancer cells. Activation of NF-κB through overexpression of c-FLIP or IKK (also known as CFLAR and IKBKB, respectively), or silencing of IκB (also known as NFKBIA), rescued EGFR-mutant lung cancer cells from EGFR TKI treatment. Genetic or pharmacologic inhibition of NF-κB enhanced erlotinib-induced apoptosis in erlotinib-sensitive and erlotinib-resistant EGFR-mutant lung cancer models. Increased expression of the NF-κB inhibitor IκB predicted for improved response and survival in EGFR-mutant lung cancer patients treated with EGFR TKI. These data identify NF-κB as a potential companion drug target, together with EGFR, in EGFR-mutant lung cancers and provide insight into the mechanisms by which tumour cells escape from oncogene dependence.
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Acknowledgements
We thank W. Pao, H. Varmus and members of the MSKCC Lung Cancer Oncogenome group for intellectual support. We thank J. Javier Sanchez for analysing human lung cancer gene expression data. We thank J. Wongvipat and E. Philips for technical assistance and W. Polkinghorn and members of the Sawyers Laboratory for critique of the manuscript. T.G.B. is supported by the MSKCC Clinical Scholars Fellowship funded by the Charles A. Dana Foundation, an ASCO YIA, and the Caine Halter Lung Cancer Research Fund/Uniting Against Lung Cancer Research Grant. C.L.S. and G.H. are Investigators of the Howard Hughes Medical Institute.
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T.G.B. and H.H. designed research, performed experiments, analysed data and co-wrote the paper. K.C., P.M., K.D., M.T. and C.C. provided reagents, performed experiments and analysed data. J.P. and V.A.M. analysed data. R.R., G.H. and C.L.S. designed research, analysed experiments and co-wrote the paper.
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Bivona, T., Hieronymus, H., Parker, J. et al. FAS and NF-κB signalling modulate dependence of lung cancers on mutant EGFR. Nature 471, 523–526 (2011). https://doi.org/10.1038/nature09870
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DOI: https://doi.org/10.1038/nature09870
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