FAS and NF-κB signalling modulate dependence of lung cancers on mutant EGFR Journal Article
| Authors: | Bivona, T. G.; Hieronymus, H.; Parker, J.; Chang, K.; Taron, M.; Rosell, R.; Moonsamy, P.; Dahlman, K.; Miller, V. A.; Costa, C.; Hannon, G.; Sawyers, C. L. |
| Article Title: | FAS and NF-κB signalling modulate dependence of lung cancers on mutant EGFR |
| 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 transient. 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. © 2011 Macmillan Publishers Limited. All rights reserved. |
| Keywords: | signal transduction; cancer survival; protein phosphorylation; treatment response; human cell; mutation; erlotinib; drug targeting; cytology; cell death; gene targeting; apoptosis; models, biological; lung neoplasms; epidermal growth factor receptor; down-regulation; lung cancer; rna interference; immunoglobulin enhancer binding protein; receptor, epidermal growth factor; enzyme activation; dose-response relationship, drug; drug resistance, neoplasm; enzyme activity; cell line, tumor; cancer resistance; biomarker; cancer cell; nf-kappa b; down regulation; gene silencing; mutant proteins; quinazolines; short hairpin rna; mutant; modulation; inhibition; signal; genes, erbb-1; antigens, cd95; i-kappa b proteins |
| Journal Title: | Nature |
| Volume: | 471 |
| Issue: | 7339 |
| ISSN: | 0028-0836 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2011-03-24 |
| Start Page: | 523 |
| End Page: | 526 |
| Language: | English |
| DOI: | 10.1038/nature09870 |
| PUBMED: | 21430781 |
| PROVIDER: | scopus |
| PMCID: | PMC3541675 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 1" - "Export Date: 23 June 2011" - "CODEN: NATUA" - "Source: Scopus" |
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