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-Cl-HIPP) phenocopied Ctbp2 deletion, decreasing tumor burden similarly to gemcitabine, and the combination of 4-Cl-HIPP and gemcitabine further synergistically suppressed tumor growth. Pharmacodynamic monitoring revealed that the 4-Cl-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.

Ctbp2是唯一可靶向的致癌转录共调节子，在最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，Ctbp2单倍剂量不足延长了生存期，废除了腹膜转移，并导致c-Myc急剧下调，这是TIC活动和PDAC中肿瘤进展的已知关键依赖性。CtBP2的小分子抑制剂，4-氯-羟基亚氨基苯基丙酮酸（4-Cl-HIPP）表型复制的Ctbp2缺失与吉西他滨相似，减轻了肿瘤负担，并且4-Cl-HIPP和吉西他滨的组合进一步协同抑制了肿瘤的生长。药效动力学监测表明，4-Cl-HIPP /吉西他滨联合治疗可诱导强劲而协同的肿瘤细胞凋亡，并在CKP PDAC肿瘤中显着下调TIC标记CD133。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有效途径，该药物可与标准疗法配合使用以限制原发性和转移性肿瘤负担。