TOPK promotes lung cancer resistance to EGFR tyrosine kinase inhibitors by phosphorylating and activating c-Jun.
TOPK promotes lung cancer resistance to EGFR tyrosine kinase inhibitors by phosphorylating and activating c-Jun.
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TOPK 通过磷酸化和激活 c-Jun 促进肺癌对 EGFR 酪氨酸激酶抑制剂的耐药性
DOI：
10.18632/oncotarget.6826
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发表时间：
2016-02-09
期刊：
影响因子：
--
通讯作者：
Li S
中科院分区：
文献类型：
--
作者：
Li Y;Yang Z;Li W;Xu S;Wang T;Wang T;Niu M;Zhang S;Jia L;Li S
靶向表皮生长因子受体（EGFR）的酪氨酸激酶抑制剂（TKI）在非鳞状非小细胞肺癌（NSCLC）中显示出有希望的临床疗效;然而，在恶性细胞中经常观察到耐药性，其作用机制在很大程度上仍未知。目前的研究表明，T淋巴因子激活的杀伤细胞来源的蛋白激酶（TOPK）在NSCLC中上调，在TKI难治性细胞中过度激活。TOPK通过转录因子AP-1组分c-Jun决定肺癌对EGFR靶向的TKI吉非替尼的反应性。TOPK直接结合并磷酸化c-Jun，从而激活AP-1靶基因（包括CCND1和CDC 2）的转录。TOPK沉默使EGFR-TKI耐药肺癌细胞对吉非替尼敏感，并增加吉非替尼在临床前肺腺癌异种移植模型中的疗效。这些发现代表了肺癌对TKI耐药的新机制，并表明TOPK可能具有作为预测生物标志物和治疗靶点的价值：TOPK靶向治疗可能与EGFR靶向治疗在肺癌中协同作用。
Tyrosine kinase inhibitors (TKIs) targeting the epidermal growth factor receptor (EGFR) have shown promising clinical efficacy in non-squamous non-small cell lung cancer (NSCLC); however, resistance is frequently observed in malignant cells, operating through a mechanism that remains largely unknown. The present study shows that T-lymphokine-activated killer cell-originated protein kinase (TOPK) is upregulated in NSCLC and excessively activated in TKI-refractory cells. TOPK dictates the responsiveness of lung cancers to the EGFR-targeted TKI gefitinib through the transcription factor AP-1 component c-Jun. TOPK binds directly to and phosphorylates c-Jun, which consequently activates the transcription of AP-1 target genes, including CCND1 and CDC2. TOPK silencing sensitizes EGFR-TKI-resistant lung cancer cells to gefitinib and increases gefitinib efficacy in preclinical lung adenocarcinoma xenograft models. These findings represent a novel mechanism of lung cancer resistance to TKIs and suggest that TOPK may have value both as a predictive biomarker and as a therapeutic target: TOPK-targeted therapy may synergize with EGFR-targeted therapy in lung cancers.