Chougoni Kranthi Kumar, Park Haemin, Damle Priyadarshan K, Mason Travis, Cheng Bo, Dcona Martin M, Szomju Barbara, Dozmorov Mikhail G, Idowu Michael O, Grossman Steven R
Keck School of Medicine and USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90033, USA.
Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, 23298, USA.
Oncogenesis. 2023 Nov 10;12(1):53. doi: 10.1038/s41389-023-00498-8.
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.
迫切需要确定胰腺导管腺癌（PDAC）新的治疗靶点。转录共调节因子C末端结合蛋白（CtBP）1和2在人类PDAC中高度过表达，在小鼠PDAC细胞系（CKP）中基于CRISPR的Ctbp2纯合缺失显著降低了肿瘤生长、减少了转移并延长了原位小鼠同种异体移植的生存期。对源自CKP与缺失Ctbp2的CKP细胞（CKP/KO）的肿瘤进行转录组分析，发现表皮生长因子受体（EGFR）超家族受体Erbb3显著下调，Erbb3是EGFR和ErbB2的异二聚体信号伴侣。与CKP细胞相比，CKP/KO细胞的Erbb2表达也降低，并且在其配体神经调节蛋白-1刺激Erbb3后未激活下游Akt信号。人类PDAC细胞系中的ErbB3表达同样依赖于CtBP2，在人类PDAC细胞系中敲除ErbB3会严重减弱细胞生长，这表明ErbB3信号在维持PDAC细胞生长中起关键作用。对ErbB2靶向酪氨酸激酶抑制剂拉帕替尼的敏感性，但对EGFR靶向药物厄洛替尼的敏感性，与小鼠和人类PDAC细胞中ErbB3表达水平成比例变化，这表明ErBb2抑制剂可以有效利用CtBP2驱动的生理性ErbB2/3表达和信号的转录激活，从而在PDAC细胞中产生治疗益处。
