Influence of Novel KGFR Tyrosine Kinase Inhibitors on KGF-mediated Proliferation of Breast Cancer

• Published in: Anticancer research 2010-12, Vol.30 (12), p.4883-4889
• Main Authors: MEHTA, Meghna, KESINGER, Jason W, ZANG, Xiao-Ping, LERNER, Megan L, BRACKETT, Daniel J, BRUEGGEMEIER, Robert W, LI, Pui-Kui, PENTO, J. Thomas
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Breast Neoplasms - drug therapy; Breast Neoplasms - enzymology; Breast Neoplasms - pathology; Cell Growth Processes - drug effects; Cell Growth Processes - physiology; Cell Line, Tumor; Extracellular Signal-Regulated MAP Kinases - metabolism; Female; Fibroblast Growth Factor 7 - antagonists & inhibitors; Fibroblast Growth Factor 7 - pharmacology; Gynecology. Andrology. Obstetrics; Humans; Indoles - pharmacology; Mammary gland diseases; MAP Kinase Signaling System - drug effects; Medical sciences; Protein Kinase Inhibitors - pharmacology; Quinolones - pharmacology; Receptor, Fibroblast Growth Factor, Type 2 - antagonists & inhibitors; Receptor, Fibroblast Growth Factor, Type 2 - metabolism; Tumors
• ISSN: 0250-7005; 1791-7530

Keratinocyte growth factor (KGF) acts at the KGF receptor (KGFR) to produce a rapid stimulation of breast cancer cell proliferation and motility which is mediated via the Erk signaling pathway. Enhancement of KGF/KGFR signal transduction may be an early step in the metastatic progression of breast cancer. Receptor modeling of KGFR was used to identify selective KGFR tyrosine kinase (TK) inhibitor molecules that have the potential to bind selectively to the KGFR. The present study evaluated the biological activity of 57 of these KGFR TK inhibitor compounds on breast cancer cells. These compounds were tested for their ability to inhibit KGF-mediated breast cancer cell proliferation in MCF-7 breast cancer cells. Furthermore, the effects of the most effective proliferation inhibitors were examined on Erk signaling and on the relative density of cell membrane KGFR. It was observed that 27 of the 57 compounds tested produced a 20% or greater reduction in KGF-mediated proliferation; while five compounds produced greater than 50% inhibition. In addition, the most potent inhibitors also reduced Erk signaling and cell membrane density of the KGFR. The compounds examined appear to be selective KGFR inhibitors which inhibit KGF-mediated activity and reduce the expression of KGFR on cancer cells. These results may lead to the development of a novel class of anticancer agents for the prevention of metastatic cancer progression.