NF-κB drives acquired resistance to a novel mutant-selective EGFR inhibitor.
NF-κB drives acquired resistance to a novel mutant-selective EGFR inhibitor.
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DOI：
10.18632/oncotarget.3956
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发表时间：
2015-12-15
期刊：
影响因子：
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通讯作者：
Giovannetti E
中科院分区：
文献类型：
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作者：
Galvani E;Sun J;Leon LG;Sciarrillo R;Narayan RS;Sjin RT;Lee K;Ohashi K;Heideman DA;Alfieri RR;Heynen GJ;Bernards R;Smit EF;Pao W;Peters GJ;Giovannetti E
EGFR酪氨酸激酶抑制剂（TKI）在携带EGFR激活突变的非小细胞肺癌（NSCLC）中的临床疗效受到获得性耐药的限制，主要归因于继发性EGFR-T790 M突变。选择性EGFR-T790 M抑制剂已被提出作为一种新的，非常相关的治疗方法。在此，我们证明了新型不可逆EGFR-TKI CNX-2006（CO-1686的结构类似物，目前在1/2期试验中进行了测试）对表达突变型EGFR的体外和体内NSCLC模型具有活性，对野生型受体的影响极小。通过整合对同基因细胞对的遗传和功能分析，我们提供了NF-κB1在驱动CNX-2006获得性耐药中发挥关键作用的证据，并表明当在T790 M突变的情况下实现对靶点的有效和持续抑制时，NF-κB激活可能取代NSCLC中的致癌EGFR信号传导。在这种情况下，我们证明了NF-κB的遗传或药理学抑制足以降低适应EGFR-TKI的细胞的活力。总体而言，我们的研究结果支持合理抑制NF-κB通路的成员，作为一种有希望的治疗选择，用于治疗新型多药选择性EGFR-TKI治疗后进展的患者。
The clinical efficacy of EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) harbouring activating EGFR mutations is limited by the emergence of acquired resistance, mostly ascribed to the secondary EGFR-T790M mutation. Selective EGFR-T790M inhibitors have been proposed as a new, extremely relevant therapeutic approach. Here, we demonstrate that the novel irreversible EGFR-TKI CNX-2006, a structural analog of CO-1686, currently tested in a phase-1/2 trial, is active against in vitro and in vivo NSCLC models expressing mutant EGFR, with minimal effect on the wild-type receptor. By integration of genetic and functional analyses in isogenic cell pairs we provide evidence of the crucial role played by NF-κB1 in driving CNX-2006 acquired resistance and show that NF-κB activation may replace the oncogenic EGFR signaling in NSCLC when effective and persistent inhibition of the target is achieved in the presence of the T790M mutation. In this context, we demonstrate that the sole, either genetic or pharmacologic, inhibition of NF-κB is sufficient to reduce the viability of cells that adapted to EGFR-TKIs. Overall, our findings support the rational inhibition of members of the NF-κB pathway as a promising therapeutic option for patients who progress after treatment with novel mutant-selective EGFR-TKIs.