Repurposing Brigatinib for the Treatment of Colorectal Cancer Based on Inhibition of ER-phagy
Repurposing Brigatinib for the Treatment of Colorectal Cancer Based on Inhibition of ER-phagy
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DOI：
10.7150/thno.36254
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发表时间：
2019-07
期刊：
影响因子：
12.4
通讯作者：
Zhe Zhang;Wei Gao;Li Zhou;Yan Chen;Siyuan Qin;Lu Zhang;Jiayang Liu;Yujia He;Yunlong Lei;Haining Chen;Junhong Han;Zongguang Zhou;E. Nice;Changlong Li;Canhua Huang;Xiawei Wei
中科院分区：
文献类型：
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作者：
Zhe Zhang;Wei Gao;Li Zhou;Yan Chen;Siyuan Qin;Lu Zhang;Jiayang Liu;Yujia He;Yunlong Lei;Haining Chen;Junhong Han;Zongguang Zhou;E. Nice;Changlong Li;Canhua Huang;Xiawei Wei
基本原理：肿瘤细胞中持续的严重内质网应激可能导致细胞凋亡，从而成为肿瘤治疗的潜在靶点。Brigatinib是一种间变性淋巴瘤激酶（ALK）抑制剂，获批用于治疗ALK阳性非小细胞肺癌（NSCLC）。然而，目前尚不清楚brigatinib是否具有在ALK阴性癌症中发挥抗肿瘤作用的替代作用模型。研究方法：ALK阳性NSCLC细胞和各种人ALK阴性癌细胞，尤其是人结直肠癌（CRC）细胞，用于检查brigatinib单独给药或与自噬抑制剂联合给药的体外和体内肿瘤抑制作用。进行了多种生化试验，以阐明brigatinib在CRC细胞中的潜在机制。结果：在此，我们通过持续ER应激诱导细胞凋亡，显示了brigatinib在CRC中的显著抗癌作用。从机制上讲，布格替尼通过促进遍在蛋白特异性肽酶5（USP 5）（一种去遍在蛋白酶）和氧固醇结合蛋白相关蛋白8（ORP 8）之间的相互作用来诱导ER应激，导致ORP 8去遍在蛋白化、积累和生长抑制。此外，我们发现brigatinib介导的ER应激通过ER-吞噬同时诱导自噬反应，作为一种保护机制，缓解过度的ER应激。因此，brigatinib与自噬抑制剂联合使用可显著增强brigatinib在体外和体内的抗CRC作用，支持brigatinib在CRC中的再利用，与ALK无关。结论：Brigatinib的新分子作用表明，ER应激和自噬的治疗性调节可能是治疗CRC和其他ALK阴性癌症的有效策略。
Rationale: The sustained and severe endoplasmic reticulum (ER) stress in cancer cells may contribute to apoptotic cell death, thus representing a potential target for cancer therapy. Brigatinib is an anaplastic lymphoma kinase (ALK) inhibitor approved for the treatment of ALK-positive non-small-cell lung cancer (NSCLC). However, it remains unclear if brigatinib has alternative model of action to exert antitumor effect in ALK-negative cancers. Methods: ALK-positive NSCLC cells and various human ALK-negative cancer cells, especially human colorectal cancer (CRC) cells were used to examine the tumor suppression effect of brigatinib alone or in combination with autophagy inhibitors in vitro and in vivo. A variety of biochemical assays were conducted to elucidate the underlying mechanisms of brigatinib in CRC cells. Results: Here, we show the significant anti-cancer effect of brigatinib in CRC through induction of apoptosis by sustained ER stress. Mechanistically, brigatinib induces ER stress via promoting the interaction between ubiquitin-specific peptidase 5 (USP5), a deubiquitinase, and oxysterol-binding protein-related protein 8 (ORP8), leading to ORP8 deubiquitination, accumulation and growth inhibition. Furthermore, we find that brigatinib-mediated ER stress simultaneously induces autophagic response via ER-phagy that acts as a protective mechanism to relieve excessive ER stress. As such, combination of brigatinib with autophagy inhibitors significantly enhances the anti-CRC effect of brigatinib both in vitro and in vivo, supporting the repurposing of brigatinib in CRC, independently of ALK. Conclusion: The unearthed new molecular action of brigatinib suggests that therapeutic modulation of ER stress and autophagy might represent a valid strategy to treat CRC and perhaps other ALK-negative cancers.