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

Cancer Research - Tập 64 Số 19 - Trang 7099-7109 - 2004
Scott M. Wilhelm1, Christopher Carter1, LiYa Tang1, Dean Wilkie1, Angela McNabola1, Hong Rong1, Charles Chen1, Xiaomei Zhang1, Patrick W. Vincent1, Mark McHugh1, Yuntai Cao1, Jaleel Shujath1, Susan L. Gawlak1, Deepa Eveleigh1, Bruce R. Rowley1, Li Liu1, Lila Adnane1, Mark Lynch1, Daniel Auclair1, I Taylor1, Rich Gedrich1, Andrei Voznesensky1, Bernd Riedl1, Leonard Post2, Gideon Bollag2, Pamela A. Trail1
11Bayer Pharmaceuticals Corporation, West Haven, Connecticut; and
22Onyx Pharmaceuticals, Richmond, California

Tóm tắt

Abstract 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 β, 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 β, 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 in two of three xenograft models examined, consistent with inhibition of the RAF/MEK/ERK pathway in some but not all models. Additional analyses of microvessel density and microvessel area in the same tumor sections using antimurine CD31 antibodies demonstrated significant inhibition of neovascularization in all three of the xenograft models. These data demonstrate that BAY 43-9006 is a novel dual action RAF kinase and VEGFR inhibitor that targets tumor cell proliferation and tumor angiogenesis.

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Cancer Research

Tập 64 Số 19

7099-7109

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