| First Author | Blakely CM | Year | 2015 |
| Journal | Cell Rep | Volume | 11 |
| Issue | 1 | Pages | 98-110 |
| PubMed ID | 25843712 | Mgi Jnum | J:228161 |
| Mgi Id | MGI:5705449 | Doi | 10.1016/j.celrep.2015.03.012 |
| Citation | Blakely CM, et al. (2015) NF-kappaB-activating complex engaged in response to EGFR oncogene inhibition drives tumor cell survival and residual disease in lung cancer. Cell Rep 11(1):98-110 |
| abstractText | 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-kappaB 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-kappaB-mediated transcriptional survival program. The direct NF-kappaB 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-kappaB activation as a critical adaptive survival mechanism engaged by EGFR oncogene inhibition and provide rationale for EGFR and NF-kappaB co-inhibition to eliminate residual disease and enhance patient responses. |
