Downregulation of death receptor 4 is tightly associated with positive response of EGFR mutant lung cancer to EGFR-targeted therapy and improved prognosis.
Downregulation of death receptor 4 is tightly associated with positive response of EGFR mutant lung cancer to EGFR-targeted therapy and improved prognosis.
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作者：
Zhang S;Chen Z;Shi P;Fan S;He Y;Wang Q;Li Y;Ramalingam SS;Owonikoko TK;Sun SY
死亡受体4 （DR4）是一种细胞表面受体，根据细胞环境的不同，通过与其配体结合介导细胞凋亡或诱导炎症细胞因子分泌。其在肺癌中的预后影响以及egfr靶向治疗与DR4调节之间的联系尚未报道，因此是本研究的重点。方法：采用Western blotting检测细胞内蛋白变化。采用抗体染色和流式细胞术检测细胞表面蛋白。采用qRT-PCR检测mRNA表达。用启动子报告子试验分析基因的转激活。使用异种移植物评估药物在体内的动态效应。通过基因过表达和敲低实现基因调控。免疫组织化学染色人档案组织蛋白。结果：EGFR抑制剂（如奥西替尼）仅在EGFR突变的NSCLC细胞和肿瘤中降低DR4水平，与诱导细胞凋亡密切相关。一旦细胞对这些抑制剂产生耐药性，这种调节就会消失。在获得性奥西替尼耐药的细胞系和egfr靶向治疗后复发的NSCLC组织中检测到DR4水平升高。在敏感和耐药细胞系中，DR4敲低与奥西替尼联合可诱导细胞凋亡和增强细胞凋亡，而强化DR4表达可显著减弱奥西替尼诱导的细胞凋亡。机制上，奥西替尼诱导march8介导的DR4蛋白酶体降解，抑制MEK/ERK/ ap -1依赖性DR4转录，导致DR4下调。此外，我们发现DR4在人肺腺癌中的阳性表达与患者生存不良显著相关。结论：总的来说，我们认为DR4下调与egfr靶向治疗的治疗效果相关，并预测预后改善，揭示了egfr靶向治疗与DR4调节之间先前未被发现的联系。
Death receptor 4 (DR4), a cell surface receptor, mediates apoptosis or induces inflammatory cytokine secretion upon binding to its ligand depending on cell contexts. Its prognostic impact in lung cancer and connection between EGFR-targeted therapy and DR4 modulation has not been reported and thus was the focus of this study. Methods: Intracellular protein alterations were measured by Western blotting. Cell surface protein was detected with antibody staining and flow cytometry. mRNA expression was monitored with qRT-PCR. Gene transactivation was analyzed with promoter reporter assay. Drug dynamic effects in vivo were evaluated using xenografts. Gene modulations were achieved with gene overexpression and knockdown. Proteins in human archived tissues were stained with immunohistochemistry. Results: EGFR inhibitors (e.g., osimertinib) decreased DR4 levels only in EGFR mutant NSCLC cells and tumors, being tightly associated with induction of apoptosis. This modulation was lost once cells became resistant to these inhibitors. Increased levels of DR4 were detected in cell lines with acquired osimertinib resistance and in NSCLC tissues relapsed from EGFR-targeted therapy. DR4 knockdown induced apoptosis and augmented apoptosis when combined with osimertinib in both sensitive and resistant cell lines, whereas enforced DR4 expression significantly attenuated osimertinib-induced apoptosis. Mechanistically, osimertinib induced MARCH8-mediated DR4 proteasomal degradation and suppressed MEK/ERK/AP-1-dependent DR4 transcription, resulting in DR4 downregulation. Moreover, we found that DR4 positive expression in human lung adenocarcinoma was significantly associated with poor patient survival. Conclusions: Collectively, we suggest that DR4 downregulation is coupled to therapeutic efficacy of EGFR-targeted therapy and predicts improved prognosis, revealing a previously undiscovered connection between EGFR-targeted therapy and DR4 modulation.
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影响因子：
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作者：
Cragg MS;Kuroda J;Puthalakath H;Huang DC;Strasser A
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通讯作者：
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Dixit, VM
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