Details

Autor(en) / Beteiligte

• 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.

Titel

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

Ist Teil von

• Cell reports (Cambridge), 2015-04, Vol.11 (1), p.98-110

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2015

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. [Display omitted] •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.