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.
authors: Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Box 20, New York, New York 10065, USA.
authors: Trever G
authors: TG
authors: Bivona
authors: Haley
authors: H
authors: Hieronymus
authors: Joel
authors: J
authors: Parker
authors: Kenneth
authors: K
authors: Chang
authors: Miquel
authors: M
authors: Taron
authors: Rafael
authors: R
authors: Rosell
authors: Philicia
authors: P
authors: Moonsamy
authors: Kimberly
authors: K
authors: Dahlman
authors: Vincent A
authors: VA
authors: Miller
authors: Carlota
authors: C
authors: Costa
authors: Gregory
authors: G
authors: Hannon
authors: Charles L
authors: CL
authors: Sawyers
mesh_terms: D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000069347:Erlotinib Hydrochloride; D018773:Genes, erbB-1 / Q000235:genetics; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D008954:Models, Biological; D050505:Mutant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D019014:fas Receptor / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D020672:I-kappa B Proteins; D050505:Mutant Proteins; D016328:NF-kappa B; D011799:Quinazolines; D019014:fas Receptor; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors