FAS and NF-kappa B signalling modulate dependence of lung cancers on mutant EGFR

Bivona, T. G., Hieronymus, H., Parker, J., Chang, K., Taron, M., Rosell, R., Moonsamy, P., Dahlman, K., Miller, V. A., Costa, C., Hannon, G. J., Sawyers, C. L. (March 2011) FAS and NF-kappa B signalling modulate dependence of lung cancers on mutant EGFR. Nature, 471 (7339). pp. 523-526. ISSN 0028-0836

URL: http://www.ncbi.nlm.nih.gov/pubmed/21430781
DOI: 10.1038/nature09870

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(1,2). 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-kappa B pathway specifically enhanced cell death induced by the EGFR TKI erlotinib in EGFR-mutant lung cancer cells. Activation of NF-kappa B through overexpression of c-FLIP or IKK (also known as CFLAR and IKBKB, respectively), or silencing of I kappa B (also known as NFKBIA), rescued EGFR-mutant lung cancer cells from EGFR TKI treatment. Genetic or pharmacologic inhibition of NF-kappa B enhanced erlotinib-induced apoptosis in erlotinib-sensitive and erlotinib-resistant EGFR-mutant lung cancer models. Increased expression of the NF-kappa B inhibitor I kappa B predicted for improved response and survival in EGFR-mutant lung cancer patients treated with EGFR TKI. These data identify NF-kappa B 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.

Item Type: Paper
Uncontrolled Keywords: acquired-resistance met amplification erlotinib mutations kinase cells adenocarcinoma inhibition gefitinib apoptosis
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > RNAi
organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > apoptosis
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > kinase
diseases & disorders > cancer > cancer types > lung cancer
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > kinase > tyrosine kinase
CSHL Authors:
Communities: CSHL Cancer Center Program > Cancer Genetics
CSHL Cancer Center Shared Resources > Bioinformatics Service
CSHL Cancer Center Shared Resources > DNA Sequencing Service
CSHL labs > Hannon lab
CSHL Cancer Center Shared Resources > Functional Genomics and Genetics Service
Depositing User: CSHL Librarian
Date: March 2011
Date Deposited: 20 Oct 2011 15:19
Last Modified: 30 Oct 2015 16:14
PMCID: PMC3541675
Related URLs:
URI: http://repository.cshl.edu/id/eprint/15605

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