CtBP-a targetable dependency for tumor-initiating cell activity and metastasis in pancreatic adenocarcinoma
CtBP-a targetable dependency for tumor-initiating cell activity and metastasis in pancreatic adenocarcinoma
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DOI：
10.1038/s41389-019-0163-x
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发表时间：
2019-10-04
期刊：
影响因子：
6.2
通讯作者：
Grossman, Steven R.
中科院分区：
文献类型：
--
作者：
Chawla, Ayesha T.;Chougoni, Kranthi Kumar;Grossman, Steven R.
Ctbp 2是一种独特的靶向致癌转录辅助调节因子，在大多数常见的实体瘤中表现出过表达，并且对肿瘤起始细胞（TIC）转录程序至关重要。在由突变K-Ras驱动的“CKP”小鼠胰腺导管腺癌（PDAC）模型中，Ctbp 2单倍不足延长存活，消除腹膜转移，并引起c-Myc的显著下调，这是PDAC中TIC活性和肿瘤进展的已知关键依赖性。CtBP 2的小分子抑制剂4-氯-羟基亚氨基苯丙酮酸（4-CI-HIPP）表型化Ctbp 2缺失，与吉西他滨类似地降低肿瘤负荷，并且4-CI-HIPP和吉西他滨的组合进一步协同抑制肿瘤生长。药效学监测显示，4-CI-HIPP/吉西他滨组合诱导了CKP PDAC肿瘤中稳健和协同的肿瘤细胞凋亡以及TIC标志物CD 133的显著下调。总的来说，我们的数据表明，靶向CtBP代表了在PDAC中开发高活性药物的富有成效的途径，这些药物与标准治疗合作，以限制原发性和转移性肿瘤负荷。
Ctbp2 is a uniquely targetable oncogenic transcriptional coregulator, exhibiting overexpression in most common solid tumors, and critical to the tumor-initiating cell (TIC) transcriptional program. In the "CKP" mouse pancreatic ductal adenocarcinoma (PDAC) model driven by mutant K-Ras, Ctbp2 haploinsufficiency prolonged survival, abrogated peritoneal metastasis, and caused dramatic downregulation of c-Myc, a known critical dependency for TIC activity and tumor progression in PDAC. A small-molecule inhibitor of CtBP2, 4-chloro-hydroxyimino phenylpyruvate (4-CI-HIPP) phenocopied Ctbp2 deletion, decreasing tumor burden similarly to gemcitabine, and the combination of 4-CI-HIPP and gemcitabine further synergistically suppressed tumor growth. Pharmacodynamic monitoring revealed that the 4-CI-HIPP/gemcitabine combination induced robust and synergistic tumor apoptosis and marked downregulation of the TIC marker CD133 in CKP PDAC tumors. Collectively, our data demonstrate that targeting CtBP represents a fruitful avenue for development of highly active agents in PDAC that cooperate with standard therapy to limit both primary and metastatic tumor burden.