迫切需要确定胰腺导管腺癌（PDAC）的新治疗弱点。转录共调控因子 C 端结合蛋白 (CtBP) 1 和 2 在人 PDAC 中高度过表达，在小鼠 PDAC 细胞系 (CKP) 中基于 CRISPR 的 Ctbp2 纯合缺失可显着降低肿瘤生长、减少转移并延长生存期在原位小鼠同种异体移植物中。 CKP 与 Ctbp2 删除的 CKP 细胞 (CKP/KO) 来源的肿瘤的转录组分析显示，EGFR 超家族受体 Erbb3（EGFR 和 ErbB2 的异二聚体信号传导伴侣）显着下调。与CKP细胞相比，CKP/KO细胞还表现出Erbb2表达降低，并且在其配体neuregulin-1刺激Erbb3后不会激活下游Akt信号传导。人 PDAC 细胞系中的 ErbB3 表达同样依赖于 CtBP2，并且人 PDAC 细胞系中 ErbB3 的消耗会严重减弱生长，这证明了 ErbB3 信号传导在维持 PDAC 细胞生长中的关键作用。对 ErbB2 靶向酪氨酸激酶抑制剂拉帕替尼（而非 EGFR 靶向药物厄洛替尼）的敏感性与小鼠和人 PDAC 细胞中 ErbB3 表达水平成比例变化，表明 ErBb2 抑制剂可以有效利用 CtBP2 驱动的转录激活PDAC 细胞中 ErbB2/3 的生理表达和信号转导以获得治疗益处。© 2023。作者。

There is a critical need to identify new therapeutic vulnerabilities in pancreatic ductal adenocarcinoma (PDAC). Transcriptional co-regulators C-terminal binding proteins (CtBP) 1 and 2 are highly overexpressed in human PDAC, and CRISPR-based homozygous deletion of Ctbp2 in a mouse PDAC cell line (CKP) dramatically decreased tumor growth, reduced metastasis, and prolonged survival in orthotopic mouse allografts. Transcriptomic profiling of tumors derived from CKP vs. Ctbp2-deleted CKP cells (CKP/KO) revealed significant downregulation of the EGFR-superfamily receptor Erbb3, the heterodimeric signaling partner for both EGFR and ErbB2. Compared with CKP cells, CKP/KO cells also demonstrated reduced Erbb2 expression and did not activate downstream Akt signaling after stimulation of Erbb3 by its ligand neuregulin-1. ErbB3 expression in human PDAC cell lines was similarly dependent on CtBP2 and depletion of ErbB3 in a human PDAC cell line severely attenuated growth, demonstrating the critical role of ErbB3 signaling in maintaining PDAC cell growth. Sensitivity to the ErbB2-targeted tyrosine kinase inhibitor lapatinib, but not the EGFR-targeted agent erlotinib, varied in proportion to the level of ErbB3 expression in mouse and human PDAC cells, suggesting that an ErBb2 inhibitor can effectively leverage CtBP2-driven transcriptional activation of physiologic ErbB2/3 expression and signaling in PDAC cells for therapeutic benefit.© 2023. The Author(s).