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• W2087955215 abstract "A substantial proportion of lung cancers in non-smokers are associated with mutations in EGFR, the gene for the epidermal growth factor receptor. EGFR tyrosine kinase inhibitors such as erlotinib are used to treat such tumours, but not all patients respond and some even develop resistance. Now, an RNA interference screen for modifiers of the EGFR inhibitor response suggests a potential strategy for improving lung cancer therapy. The screen reveals that inhibition of CD95/Fas and NF- B signalling enhances the response to EGRF inhibitors in vitro and in vivo. In patients with lung cancer who are treated with EGFR inhibitors, expression of the NF-κB inhibitor IκB is associated with a better response and longer survival, suggesting that combining NF-κB pathway and EGFR inhibitors may prove clinically useful. Lung cancers with activating mutations in EGFR can be treated with EGFR inhibitors, but not all tumours respond and some develop resistance. In an RNAi screen, this study searches for modifiers of the EGFR inhibitor response. It is found that inhibition of FAS and NF-κB signalling enhances the response in vitro and in vivo. In a cohort of lung cancer patients treated with EGFR inhibitors, expression of the NF-κB inhibitor IκB is associated with a better response and longer survival, indicating that combining NF-κB pathway and EGFR inhibitors may prove clinically useful. 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." @default.
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• W2087955215 date "2011-03-01" @default.
• W2087955215 modified "2023-10-10" @default.
• W2087955215 title "FAS and NF-κB signalling modulate dependence of lung cancers on mutant EGFR" @default.
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• W2087955215 doi "https://doi.org/10.1038/nature09870" @default.
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