Antitumour activity of a potent MEK inhibitor RDEA119/BAY 869766 combined with rapamycin in human orthotopic primary pancreatic cancer xenografts.

Abstract

BACKGROUND:

Combining MEK inhibitors with other signalling pathway inhibitors or conventional cytotoxic drugs represents a promising new strategy against cancer. RDEA119/BAY 869766 is a highly potent and selective MEK1/2 inhibitor undergoing phase I human clinical trials. The effects of RDEA119/BAY 869766 as a single agent and in combination with rapamycin were studied in 3 early passage primary pancreatic cancer xenografts, OCIP19, 21, and 23, grown orthotopically.

METHODS:

Anti-cancer effects were determined in separate groups following chronic drug exposure. Effects on cell cycle and downstream signalling were examined by flow cytometry and western blot, respectively. Plasma RDEA119 concentrations were measured to monitor the drug accumulation in vivo.

RESULTS:

RDEA119/BAY 869766 alone or in combination with rapamycin showed significant growth inhibition in all the 3 models, with a significant decrease in the percentage of cells in S-phase, accompanied by a large decrease in bromodeoxyuridine labelling and cell cycle arrest predominantly in G1. The S6 ribosomal protein was inhibited to a greater extent with combination treatment in all the three models. Blood plasma pharmacokinetic analyses indicated that RDEA119 levels achieved in vivo are similar to those that produce target inhibition and cell cycle arrest in vitro.

CONCLUSIONS:

Agents targeting the ERK and mTOR pathway have anticancer activity in primary xenografts, and these results support testing this combination in pancreatic cancer patients.

• Authors: Qing Chang, Mark S Chapman, Jeffrey N Miner, David W Hedley
• Journal: BMC cancer (BMC Cancer) Vol. 10 Pg. 515 (Sep 28 2010) ISSN: 1471-2407 [Electronic] England
• PMID: 20920162 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Enzyme Inhibitors
• N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide
• Sulfonamides
• Diphenylamine
• MAP Kinase Kinase Kinases
• Bromodeoxyuridine
• Sirolimus

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Bromodeoxyuridine (pharmacology)
• Cell Cycle
• Cell Line, Tumor
• Diphenylamine (administration & dosage, analogs & derivatives)
• Enzyme Inhibitors (pharmacology)
• Humans
• MAP Kinase Kinase Kinases (antagonists & inhibitors)
• Male
• Mice
• Neoplasm Transplantation
• Pancreatic Neoplasms (drug therapy)
• Signal Transduction
• Sirolimus (administration & dosage)
• Sulfonamides (administration & dosage)