| Autor: |
Collin M. Blakely, Evangelos Pazarentzos, Victor Olivas, Saurabh Asthana, Jenny Jiacheng Yan, Irena Tan, Gorjan Hrustanovic, Elton Chan, Luping Lin, Dana S. Neel, William Newton, Kathryn L. Bobb, Timothy R. Fouts, Jeffrey Meshulam, Matthew A. Gubens, David M. Jablons, Jeffrey R. Johnson, Sourav Bandyopadhyay, Nevan J. Krogan, Trever G. Bivona |
| Jazyk: |
angličtina |
| Rok vydání: |
2015 |
| Předmět: |
|
| Zdroj: |
Cell Reports, Vol 11, Iss 1, Pp 98-110 (2015) |
| Druh dokumentu: |
article |
| ISSN: |
2211-1247 |
| DOI: |
10.1016/j.celrep.2015.03.012 |
| Popis: |
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. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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