Coordinate transcriptional regulation of ErbB2/3 by C-terminal binding protein 2 signals sensitivity to ErbB2 inhibition in pancreatic adenocarcinoma

• Published in: Oncogenesis (New York, NY) Vol. 12; no. 1; p. 53
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 10.11.2023; Nature Publishing Group
• Subjects: 13/1; 13/106; 13/51; 13/95; 14/5; 38; 38/91; 631/67/1059/602; 631/67/1504/1713; 631/67/1857; 631/67/70; 64/60; 96; 96/21; Adenocarcinoma; AKT protein; Apoptosis; Brief Communication; Cell Biology; CRISPR; Down-regulation; Epidermal growth factor receptors; ErbB-2 protein; ErbB-3 protein; Gene deletion; Gene regulation; Human Genetics; Internal Medicine; Kinases; Medicine; Medicine & Public Health; Metastases; Neuregulin 1; Oncology; Pancreas; Pancreatic cancer; Protein-tyrosine kinase; Transcription activation; Transcriptomics
• ISSN: 2157-9024; 2157-9024
• 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.