NF-κB-Activating Complex Engaged in Response to EGFR Oncogene Inhibition Drives Tumor Cell Survival and Residual Disease in Lung Cancer

• Published in: Cell reports (Cambridge) Vol. 11; no. 1; pp. 98 - 110
• Main Authors: Blakely, Collin M., Pazarentzos, Evangelos, Olivas, Victor, Asthana, Saurabh, Yan, Jenny Jiacheng, Tan, Irena, Hrustanovic, Gorjan, Chan, Elton, Lin, Luping, Neel, Dana S., Newton, William, Bobb, Kathryn L., Fouts, Timothy R., Meshulam, Jeffrey, Gubens, Matthew A., Jablons, David M., Johnson, Jeffrey R., Bandyopadhyay, Sourav, Krogan, Nevan J., Bivona, Trever G.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 07-04-2015; Elsevier
• Subjects: Adenocarcinoma - drug therapy; Adenocarcinoma - genetics; Adenocarcinoma - pathology; Adenocarcinoma of Lung; Antineoplastic Agents - administration & dosage; Apoptosis - drug effects; Cell Line, Tumor; Cell Survival - drug effects; Cyclohexanones - administration & dosage; Drug Resistance, Neoplasm - genetics; Epoxy Compounds - administration & dosage; ErbB Receptors - antagonists & inhibitors; ErbB Receptors - genetics; Gene Expression Regulation, Neoplastic - drug effects; Humans; I-kappa B Kinase - genetics; I-kappa B Kinase - metabolism; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Molecular Targeted Therapy; NF-kappa B - antagonists & inhibitors; NF-kappa B - genetics; Nuclear Pore Complex Proteins - genetics; Nuclear Pore Complex Proteins - metabolism; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; Signal Transduction - drug effects; TNF Receptor-Associated Factor 2 - genetics; TNF Receptor-Associated Factor 2 - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2015.03.012

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.
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•NF-κB is activated early in response to EGFR oncogene-targeted therapy•EGFR inhibition adaptively promotes formation of an NF-κB-activating complex•Adaptive NF-κB signaling drives tumor cell survival and residual disease•NF-κB inhibition via PBS-1086 combats tumor cell survival and residual disease
Blakely et al. reveal that NF-κB signaling is acutely activated in response to EGFR oncogene inhibition in lung cancer via a complex that promotes tumor cell survival and residual disease. They uncover a direct pharmacologic NF-κB inhibitor that overrides this adaptive survival mechanism and may enhance patient outcomes.