Cancer stem cell-related gene expression as a potential biomarker of response for first-in-class imipridone ONC201 in solid tumors.
Cancer stem cell-related gene expression as a potential biomarker of response for first-in-class imipridone ONC201 in solid tumors.
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DOI：
10.1371/journal.pone.0180541
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
El-Deiry WS
中科院分区：
文献类型：
--
作者：
Prabhu VV;Lulla AR;Madhukar NS;Ralff MD;Zhao D;Kline CLB;Van den Heuvel APJ;Lev A;Garnett MJ;McDermott U;Benes CH;Batchelor TT;Chi AS;Elemento O;Allen JE;El-Deiry WS
在临床研究中，癌症干细胞（CSCs）与复发、转移和不良生存相关。癌症干细胞抑制剂的临床试验所取得的令人鼓舞的结果进一步证实了癌症干细胞可作为治疗靶点。ONC201是一种处于I/II期临床试验用于治疗晚期癌症的首创小分子吡咯并嘧啶类药物。我们先前已表明，ONC201通过抑制Akt/ERK以及诱导DR5/TRAIL来靶向具有自我更新能力且对化疗耐药的结直肠癌干细胞。在本研究中，我们证明ONC201的抗癌症干细胞效应涉及在诱导肿瘤细胞死亡之前干细胞相关基因表达的早期变化。对结直肠癌细胞基因表达谱的靶向网络分析显示，ONC201下调诸如Wnt信号通路等干细胞通路，并调节已知在结直肠癌、前列腺癌和胶质母细胞瘤中调控自我更新的基因（ID1、ID2、ID3和ALDH7A1）。ONC201介导的癌症干细胞相关基因表达的变化在每种肿瘤类型的RNA和蛋白质水平上都得到了验证。因此，我们观察到在ONC201治疗后，前列腺癌细胞系和源自患者的胶质母细胞瘤细胞的自我更新和癌症干细胞标志物受到抑制。有趣的是，在对ONC201产生获得性耐药的结直肠癌细胞中，ONC201介导的癌症干细胞耗竭不会发生。最后，我们观察到在1000多种癌细胞系中，癌症干细胞相关基因（ID1、CD44、HES7和TCF3）的基础表达与ONC201的疗效显著相关，并且综合多个基因的表达可得出更强的总体预测。这些概念验证研究为在正在进行的临床研究中检测RNA和蛋白质水平的癌症干细胞表达作为ONC201反应的预测性和药效学生物标志物提供了理论依据。
Cancer stem cells (CSCs) correlate with recurrence, metastasis and poor survival in clinical studies. Encouraging results from clinical trials of CSC inhibitors have further validated CSCs as therapeutic targets. ONC201 is a first-in-class small molecule imipridone in Phase I/II clinical trials for advanced cancer. We have previously shown that ONC201 targets self-renewing, chemotherapy-resistant colorectal CSCs via Akt/ERK inhibition and DR5/TRAIL induction. In this study, we demonstrate that the anti-CSC effects of ONC201 involve early changes in stem cell-related gene expression prior to tumor cell death induction. A targeted network analysis of gene expression profiles in colorectal cancer cells revealed that ONC201 downregulates stem cell pathways such as Wnt signaling and modulates genes (ID1, ID2, ID3 and ALDH7A1) known to regulate self-renewal in colorectal, prostate cancer and glioblastoma. ONC201-mediated changes in CSC-related gene expression were validated at the RNA and protein level for each tumor type. Accordingly, we observed inhibition of self-renewal and CSC markers in prostate cancer cell lines and patient-derived glioblastoma cells upon ONC201 treatment. Interestingly, ONC201-mediated CSC depletion does not occur in colorectal cancer cells with acquired resistance to ONC201. Finally, we observed that basal expression of CSC-related genes (ID1, CD44, HES7 and TCF3) significantly correlate with ONC201 efficacy in >1000 cancer cell lines and combining the expression of multiple genes leads to a stronger overall prediction. These proof-of-concept studies provide a rationale for testing CSC expression at the RNA and protein level as a predictive and pharmacodynamic biomarker of ONC201 response in ongoing clinical studies.
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影响因子：
64.5
作者：
Gujral TS;Chan M;Peshkin L;Sorger PK;Kirschner MW;MacBeath G
通讯作者：
MacBeath G
影响因子：
7.3
作者：
Ishizawa J;Kojima K;Chachad D;Ruvolo P;Ruvolo V;Jacamo RO;Borthakur G;Mu H;Zeng Z;Tabe Y;Allen JE;Wang Z;Ma W;Lee HC;Orlowski R;Sarbassov dos D;Lorenzi PL;Huang X;Neelapu SS;McDonnell T;Miranda RN;Wang M;Kantarjian H;Konopleva M;Davis RE;Andreeff M
通讯作者：
Andreeff M
影响因子：
50.3
作者：
O'Brien, Catherine A.;Kreso, Antonija;Dick, John E.
通讯作者：
Dick, John E.
影响因子：
11.2
作者：
Jin, Xun;Jeon, Hee-Young;Kim, Hyunggee
通讯作者：
Kim, Hyunggee
影响因子：
7.3
作者：
Kline CL;Van den Heuvel AP;Allen JE;Prabhu VV;Dicker DT;El-Deiry WS
通讯作者：
El-Deiry WS