Mole Sele

Downlo inhibitors are under clinical investigation, specifically in patients with tumor types harboring frequent ting mutations in B-Raf. Here, we show that cell lines and tumors harboring mutant B-Raf were sento a novel series of Raf inhibitors (e.g., B-Raf A375, IC50 on cells = 2 nmol/L; ED50 on tumor rafts = 1.3 mg/kg). However, in cells and tumors with wild-type B-Raf, exposure to Raf inhibitors d in a dose-dependent and sustained activation of mitogen-activated protein kinase signaling. In some e cell lines, Raf inhibition led to entry into the cell cycle, enhanced proliferation, and significantly stimtumor growth in vivo. Inhibition with structurally distinct Raf inhibitors or isoform-specific small interRNA knockdown of Raf showed that these effects were mediated directly through Raf. Either A-Raf or mediated the Raf inhibitor–induced mitogen-activated protein kinase pathway activation in an inhibiecific manner. These paradoxical effects of Raf inhibition were seen in malignant and normal cells in vitro vivo. Hyperplasia of normal epithelial cells in the esophagus and the stomach was evident in mice with and in all efficacious Raf inhibitors (n = 8) tested. An implication of these results is that Raf inhibitors may induce unexpected normal cell and tumor tissue proliferation in patients. Mol Cancer Ther; 9(8); 2399–410. ©2010 AACR.