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: 41.46). 03/2011; 471(7339):523-6. DOI: 10.1038/nature09870
Source: PubMed


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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    • "The 11–18 tumor xenografts were generated as previously described (Bivona et al., 2011). For genetically engineered mouse model (GEMM) studies, male and female mice of the desired genotype were treated with doxycycline at 6–8 weeks of age, and tumor-bearing mice were treated with the indicated compounds at 16–18 weeks of age. "
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    Cell Reports 04/2015; 465(1). DOI:10.1016/j.celrep.2015.03.012 · 8.36 Impact Factor
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    • "The majority of resistance to EGFR-TKIs are seen with: 1) the second-site exon 20 EGFR gatekeeper mutation plasmid T790M that reduces drug binding in ~50% of all cases of EGFR mutation;21 2) the plasmid T790M mutation plus EGFR amplification in ~8% of cases;22 3) tyrosine kinase switching or receptor dimerization through MET (proto-oncogene that encodes a protein known as hepatocyte growth factor receptor) amplification in ~5%–19% of cases;23 4) overexpression of AXL (encodes tyrosine-protein kinase receptor UFO in human) and its ligand GAS6 in 20% and 25% of cases, respectively;24 and 5) activating mutation of the phosphatidylinositol 3-kinase (PI3K) p110α-encoding gene PIK3CA in ~5% of cases.25–27 There is also evidence of nuclear factor-κB(NF-κB) signaling being implicated as a resistance mechanism to avoid TKI-induced apoptosis, possibly through the low expression of the NF-κB inhibitory protein IκB.25 "
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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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