Compound NSC84167 selectively targets NRF2-activated pancreatic cancer by inhibiting asparagine synthesis pathway.
Compound NSC84167 selectively targets NRF2-activated pancreatic cancer by inhibiting asparagine synthesis pathway.
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DOI：
10.1038/s41419-021-03970-8
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发表时间：
2021-07-10
影响因子：
9
通讯作者：
Fleming JB
中科院分区：
文献类型：
--
作者：
Dai B;Augustine JJ;Kang Y;Roife D;Li X;Deng J;Tan L;Rusling LA;Weinstein JN;Lorenzi PL;Kim MP;Fleming JB
核因子红细胞2相关因子2（NRF 2）在约93%的胰腺癌中异常激活。活化的NRF 2调节参与癌细胞代谢重编程、翻译控制和治疗抗性的多个下游分子;然而，靶向NRF 2用于胰腺癌治疗在很大程度上仍未探索。在这项研究中，我们使用在线计算工具CellMinerTM来探索NCI-60药物数据库中具有抗癌活性的化合物，这些化合物与NQO 1的mRNA表达最密切相关，NQO 1是NRF 2途径活性的标志物。在分析的> 100，000种化合物中，NSC 84167（本文称为NRF 2合成致死性化合物-01（NSLC 01））是最高命中之一（r = 0.71，P < 0.001）并被选择用于功能表征。NSLC 01选择性地抑制7种常规胰腺癌细胞系中的4种的活力，并在具有高NRF 2活化的细胞中诱导显著的凋亡。NSLC 01的选择性抗癌活性用一组9种低传代胰腺患者来源的细胞系进一步验证，证实了NSLC 01的log（IC 50）与NQO 1表达之间的显著负相关性（r =-0.5563，P = 0.024）。值得注意的是，对一组9个患者来源的异种移植物（PDX）的筛选揭示了6个具有高NQO 1/NRF 2活化的PDX，并且NSLC 01显著抑制PDX肿瘤的离体培养物中的活力并诱导细胞凋亡。与离体结果一致，NSLC 01在体内抑制两种NRF 2激活的PDX模型的肿瘤生长（P < 0.01，n = 7-8），但对NRF 2低对应物没有影响。为了表征作用机制，我们采用了代谢组学同位素示踪试验，证明NSLC 01介导的多种氨基酸（包括天冬酰胺和甲硫氨酸）从头合成的抑制。重要的是，我们进一步发现NSLC 01抑制eEF 2K/eEF 2翻译延长级联和天冬酰胺合成酶的蛋白质翻译。总之，这项研究确定了一种新的化合物，它选择性地靶向蛋白质翻译，并在NRF 2激活的胰腺癌中诱导合成致死效应。
Nuclear factor erythroid 2-related factor 2 (NRF2) is aberrantly activated in about 93% of pancreatic cancers. Activated NRF2 regulates multiple downstream molecules involved in cancer cell metabolic reprogramming, translational control, and treatment resistance; however, targeting NRF2 for pancreatic cancer therapy remains largely unexplored. In this study, we used the online computational tool CellMinerTM to explore the NCI-60 drug databases for compounds with anticancer activities correlating most closely with the mRNA expression of NQO1, a marker for NRF2 pathway activity. Among the >100,000 compounds analyzed, NSC84167, termed herein as NRF2 synthetic lethality compound-01 (NSLC01), was one of the top hits (r = 0.71, P < 0.001) and selected for functional characterization. NSLC01 selectively inhibited the viabilities of four out of seven conventional pancreatic cancer cell lines and induced dramatic apoptosis in the cells with high NRF2 activation. The selective anticancer activity of NSLC01 was further validated with a panel of nine low-passage pancreatic patient-derived cell lines, and a significant reverse correlation between log(IC50) of NSLC01 and NQO1 expression was confirmed (r = −0.5563, P = 0.024). Notably, screening of a panel of nine patient-derived xenografts (PDXs) revealed six PDXs with high NQO1/NRF2 activation, and NSLC01 dramatically inhibited the viabilities and induced apoptosis in ex vivo cultures of PDX tumors. Consistent with the ex vivo results, NSLC01 inhibited the tumor growth of two NRF2-activated PDX models in vivo (P < 0.01, n = 7–8) but had no effects on the NRF2-low counterpart. To characterize the mechanism of action, we employed a metabolomic isotope tracer assay that demonstrated that NSLC01-mediated inhibition of de novo synthesis of multiple amino acids, including asparagine and methionine. Importantly, we further found that NSLC01 suppresses the eEF2K/eEF2 translation elongation cascade and protein translation of asparagine synthetase. In summary, this study identified a novel compound that selectively targets protein translation and induces synthetic lethal effects in NRF2-activated pancreatic cancers.
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影响因子：
10.3
作者：
Liu, Yang;Lu, Yanxin;Yang, Chunzhang
通讯作者：
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作者：
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作者：
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通讯作者：
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