%0 Journal Article
%T TLN-4601 suppresses growth and induces apoptosis of pancreatic carcinoma cells through inhibition of Ras-ERK MAPK signaling
%A Paul M Campbell
%A Nadia Boufaied
%A James J Fiordalisi
%A Adrienne D Cox
%A Pierre Falardeau
%A Channing J Der
%A Henriette Gourdeau
%J Journal of Molecular Signaling
%D 2010
%I Ubiquity Press
%R 10.1186/1750-2187-5-18
%X 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.These data, together with phase I/II clinical data showing tolerability of TLN-4601, support conducting a clinical trial in advanced pancreatic cancer patients.Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death in North America and has a five-year survival rate of less than 5% [1]. Most patients with pancreatic cancer will die within six months of initial diagnosis. This poor prognosis has been related to the difficulty of detection in early stages of development, resulting in advanced disease at the time of presentation of first symptoms.To acquire malignancy, pancreatic ductal epithelial cells undergo a series of sequential genetic mutations. Among the initial events are KRAS mutations and HER-2/neu amplification, followed by the loss of p16INK4A/CDKN2 expression and then inactivation of p53 and DPC4/SMAD4 [2-4]. KRAS mutations occur in almost all cases of pancreatic cancer. The most common alterations are substitutions at the codon 12 glycine, producing constitutively active K-Ras [4-6]. K-Ras is a small GTPase that is a key player in various signaling pathways, working as a molecular switch to transmit signals from the cell membrane to the cytoplasm and nucleus [7,8]. A variety of extracellular signals (hormones and growth factors) activate Ras by causing the exchange of GDP with GTP. In one of the canonical signaling pathways, K-Ras recruits Raf kinases (Raf-1, B-Raf, or A-Raf) to the cell membrane where their own activation takes place. Once activated, Raf phosphorylates mitogen-activated protein kinases (MEK
%U http://www.jmolecularsignaling.com/content/5/1/18