Article

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

Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Box 20, New York, New York 10065, USA.
Nature (Impact Factor: 42.35). 03/2011; 471(7339):523-6. DOI: 10.1038/nature09870
Source: PubMed

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.

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Available from: Carlota Costa, Aug 26, 2015
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    • "Results revealed a potentially important role for nuclear factor kappa-light-chain-enhancer of activated B cells (NF-jB) signalling in regulating EGFR oncogene dependence in EGFR-mutant NSCLC. Genetic or pharmacological inhibition of NF-jB significantly enhanced responses to erlotinib in in vitro and in vivo models of EGFR-mutant NSCLC [31]. Furthermore, clinical studies using EGFR-mutant NSCLC specimens from erlotinibtreated patients showed that NF-jB hyperactivation, as marked by low tumour levels of IjB, predicted worse response and survival than for patients treated with chemotherapy. "
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    • "Nevertheless, additional examples of synthetic lethality of proteases with oncogenes have been found over the last few years. Thus, Bivona et al. (2011) carried out a screen with a shRNA library targeting approximately 2,000 cancer-related genes to identify proteins whose ablation rendered lung cancer cells sensitive to EGFR inhibition. Interestingly, besides components of the FAS and NF-kB pathway, the list of proteins identified in this study includes PSMD14 (also known as POH1/RPN11), a deubiquitinating enzyme component of the proteasome that has been involved in regulation of the ErbB2 receptor (Liu et al., 2009). "
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