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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    • "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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    ABSTRACT: Although oncogene-targeted therapy often elicits profound initial tumor responses in patients, responses are generally incomplete because some tumor cells survive initial therapy as residual disease that enables eventual acquired resistance. The mechanisms underlying tumor cell adaptation and survival during initial therapy are incompletely understood. Here, through the study of EGFR mutant lung adenocarcinoma, we show that NF-κB signaling is rapidly engaged upon initial EGFR inhibitor treatment to promote tumor cell survival and residual disease. EGFR oncogene inhibition induced an EGFR-TRAF2-RIP1-IKK complex that stimulated an NF-κB-mediated transcriptional survival program. The direct NF-κB inhibitor PBS-1086 suppressed this adaptive survival program and increased the magnitude and duration of initial EGFR inhibitor response in multiple NSCLC models, including a patient-derived xenograft. These findings unveil NF-κB activation as a critical adaptive survival mechanism engaged by EGFR oncogene inhibition and provide rationale for EGFR and NF-κB co-inhibition to eliminate residual disease and enhance patient responses. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 04/2015; 465(1). DOI:10.1016/j.celrep.2015.03.012 · 8.36 Impact Factor
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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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    ABSTRACT: Introduction: Treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) yields tumour responses in non-small cell lung cancer (NSCLC) patients harbouring activating EGFR mutations. However, even in long-lasting responses, resistance to EGFR TKIs invariably occurs. Areas covered: This review examines resistance mechanisms to EGFR TKI treatment, which mainly arise from secondary EGFR mutations. Other resistance-inducing processes include mesenchymal-epithelial transition factor (MET) amplification, epithelial-mesenchymal transformation, phenotypic change from NSCLC to small-cell lung carcinoma, and modifications in parallel signalling pathways. Current therapeutic strategies to overcome these EGFR TKI resistance mechanisms focus on the inhibition or blocking of multiple members of the ErbB family. Several molecules which target multiple ErbB receptors are being investigated in NSCLC and other indications including afatinib, an ErbB Family Blocker, as well as dacomitinib and lapatinib. Novel, non-quinazoline, EGFR inhibitors, that also target EGFR activating and resistance (T790M) mutations, are currently under clinical development. Other therapeutic strategies include inhibition of parallel and downstream pathways, using agents which target heat shock protein (HSP)90 or poly (ADP-ribose) polymerase in addition to mammalian target of rapamycin (mTOR), monoclonal antibodies against the insulin-like growth factor-1 receptor, and fulvestrant-mediated oestrogen receptor regulation. Conclusion: Improved understanding of mechanisms underlying resistance to EGFR TKIs emphasises the importance of a genotype-guided approach to therapy. Elucidation of resistance mechanisms is indeed crucial to target innovative therapeutic approaches and to improve the efficacy of anticancer regimes in NSCLC.
    Cancer Treatment Reviews 06/2014; 40(8). DOI:10.1016/j.ctrv.2014.05.009 · 6.47 Impact Factor
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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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    ABSTRACT: The "oncogene addiction" concept refers to the dependence of cancer cells on the function of the oncogenes responsible for their transformed phenotype, while the term "non-oncogene addiction" has been introduced to define the exacerbated necessity of the normal function of non-mutated genes. In this Perspective, we focus on the importance of proteolytic enzymes to maintain the viability of cancer cells and hypothesize that most, if not all, tumors present "addiction" to a number of proteolytic activities, which in turn may represent valuable targets of anti-cancer therapies, even without being mutated or over-expressed by the malignant cells.
    Frontiers in Oncology 09/2011; 1:25. DOI:10.3389/fonc.2011.00025
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