BAY 43-9006 Exhibits Broad Spectrum Oral Antitumor Activity and Targets the RAF/MEK/ERK Pathway and Receptor Tyrosine Kinases Involved in Tumor Progression and Angiogenesis

作者：Scott M. Wilhelm, Christopher Carter, LiYa Tang, Dean Wilkie, Angela McNabola, Hong Rong, Charles Chen, Xiaomei Zhang, Patrick W. Vincent, Mark McHugh, Yichen Cao, Jaleel Shujath, Susan L. Gawlak, Deepa Eveleigh, Bruce R. Rowley, Li Liu, Lila Adnane, Mark Lynch, Daniel Auclair, I Taylor, Rich Gedrich, Andrei Voznesensky, Bernd Riedl, Leonard Post, Gideon Bollag, Pamela A. Trail · 发表于：Cancer Research · 年份：2004 · DOI：10.1158/0008-5472.can-04-1443 · 被引用次数：4048 · 研究领域：Melanoma and MAPK Pathways、Protein Kinase Regulation and GTPase Signaling、Cytokine Signaling Pathways and Interactions

The RAS/RAF signaling pathway is an important mediator of tumor cell proliferation and angiogenesis. The novel bi-aryl urea BAY 43-9006 is a potent inhibitor of Raf-1, a member of the RAF/MEK/ERK signaling pathway. Additional characterization showed that BAY 43-9006 suppresses both wild-type and V599E mutant BRAF activity in vitro. In addition, BAY 43-9006 demonstrated significant activity against several receptor tyrosine kinases involved in neovascularization and tumor progression, including vascular endothelial growth factor receptor (VEGFR)-2, VEGFR-3, platelet-derived growth factor receptor beta, Flt-3, and c-KIT. In cellular mechanistic assays, BAY 43-9006 demonstrated inhibition of the mitogen-activated protein kinase pathway in colon, pancreatic, and breast tumor cell lines expressing mutant KRAS or wild-type or mutant BRAF, whereas non-small-cell lung cancer cell lines expressing mutant KRAS were insensitive to inhibition of the mitogen-activated protein kinase pathway by BAY 43-9006. Potent inhibition of VEGFR-2, platelet-derived growth factor receptor beta, and VEGFR-3 cellular receptor autophosphorylation was also observed for BAY 43-9006. Once daily oral dosing of BAY 43-9006 demonstrated broad-spectrum antitumor activity in colon, breast, and non-small-cell lung cancer xenograft models. Immunohistochemistry demonstrated a close association between inhibition of tumor growth and inhibition of the extracellular signal-regulated kinases (ERKs) 1/2 phosphorylation i...