NF-κB-activating complex engaged in response to EGFR oncogene inhibition drives tumor cell survival and residual disease in lung cancer.
NF-κB-activating complex engaged in response to EGFR oncogene inhibition drives tumor cell survival and residual disease in lung cancer.
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响应于EGFR癌基因抑制作用的NF-κB激活复合物驱动肺癌的肿瘤细胞存活和残留疾病。
DOI：
10.1016/j.celrep.2015.03.012
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发表时间：
2015-04-07
期刊：
影响因子：
8.8
通讯作者：
Bivona TG
中科院分区：
文献类型：
--
作者：
Blakely CM;Pazarentzos E;Olivas V;Asthana S;Yan JJ;Tan I;Hrustanovic G;Chan E;Lin L;Neel DS;Newton W;Bobb KL;Fouts TR;Meshulam J;Gubens MA;Jablons DM;Johnson JR;Bandyopadhyay S;Krogan NJ;Bivona TG
虽然癌基因靶向治疗通常在患者中产生深刻的初始肿瘤反应，但反应通常是不完全的，因为一些肿瘤细胞作为残留疾病在初始治疗中存活，从而最终获得耐药性。在初始治疗期间肿瘤细胞适应和存活的潜在机制尚未完全理解。在此，通过对EGFR突变型肺腺癌的研究，我们发现NF-κB信号在EGFR抑制剂治疗后迅速参与，促进肿瘤细胞存活和残留疾病。EGFR癌基因抑制诱导EGFR-TRAF 2-RIP 1-IKK复合物，该复合物刺激NF-κ B介导的转录存活程序。直接NF-κB抑制剂PBS-1086抑制了这种适应性生存程序，并增加了多种NSCLC模型（包括患者来源的异种移植物）中初始EGFR抑制剂反应的幅度和持续时间。这些发现揭示了NF-κB激活是EGFR癌基因抑制参与的关键适应性生存机制，并为EGFR和NF-κB共抑制消除残留疾病和增强患者反应提供了理论基础。
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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BIM的诱导对于突变体EGFR依赖性肺腺癌中EGFR激酶抑制剂触发的凋亡至关重要。
影响因子：
15.8
作者：
Gong, Yixuan;Somwar, Romel;Politi, Katerina;Balak, Marissa;Chmielecki, Juliann;Jiang, Xuejun;Pao, William
通讯作者：
Pao, William
DOI：
10.1186/bcr1680
发表时间：
2007
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Berishaj M;Gao SP;Ahmed S;Leslie K;Al-Ahmadie H;Gerald WL;Bornmann W;Bromberg JF
通讯作者：
Bromberg JF
影响因子：
51.1
作者：
Miller, Vincent A.;Hirsh, Vera;Yang, James Chih-Hsin
通讯作者：
Yang, James Chih-Hsin
影响因子：
16
作者：
Ea, CK;Deng, L;Chen, ZJJ
通讯作者：
Chen, ZJJ
影响因子：
4.8
作者：
Jiang, Zhilong;Clemens, Paula R.
通讯作者：
Clemens, Paula R.