Research Articles
TLN-4601 suppresses growth and induces apoptosis of pancreatic carcinoma cells through inhibition of Ras-ERK MAPK signaling
Authors:
- Paul M CampbellEmail Paul M Campbell
- Nadia Boufaied
- James J Fiordalisi
- Adrienne D Cox
- Pierre Falardeau
- Channing J Der
- Henriette Gourdeau
Abstract
Background: TLN-4601 is a structurally novel farnesylated dibenzodiazepinone discovered using Thallion’s proprietary DECIPHER® technology, a genomics and bioinformatics platform that predicts the chemical structures of secondary metabolites based on gene sequences obtained by scanning bacterial genomes. Our recent studies suggest that TLN-4601 inhibits the Ras-ERK MAPK pathway post Ras prenylation and prior to MEK activation. The Ras-ERK MAPK signaling pathway is a well-validated oncogenic cascade based on its central role in regulating the growth and survival of cells from a broad spectrum of human tumors. Furthermore, RAS isoforms are the most frequently mutated oncogenes, occurring in approximately 30% of all human cancers, and KRAS is the most commonly mutated RAS gene, with a greater than 90% incidence of mutation in pancreatic cancer.
Results: To evaluate whether TLN-4601 interferes with K-Ras signaling, we utilized human pancreatic epithelial cells and demonstrate that TLN-4601 treatment resulted in a dose- and time-dependent inhibition of Ras-ERK MAPK signaling. The compound also reduced Ras-GTP levels and induced apoptosis. Finally, treatment of MIA PaCa-2 tumor-bearing mice with TLN-4601 resulted in antitumor activity and decreased tumor Raf-1 protein levels.
Conclusion: These data, together with phase I/II clinical data showing tolerability of TLN-4601, support conducting a clinical trial in advanced pancreatic cancer patients.
- Year: 2010
- Volume: 5
- Page/Article: Art. 18
- DOI: 10.1186/1750-2187-5-18
- Submitted on 4 Aug 2010
- Accepted on 2 Nov 2010
- Published on 2 Nov 2010
- Peer Reviewed