Antitumor Efficacy of the Novel RAF Inhibitor GDC-0879 Is Predicted by BRAFV600E Mutational Status and Sustained Extracellular Signal-Regulated Kinase/Mitogen-Activated Protein Kinase Pathway Suppression

摘要: Oncogenic activation of the BRAF serine/threonine kinase has been associated with initiation and maintenance melanoma tumors. As such, development pharmacologic agents to target RAF proteins or their effector kinases is an area intense investigation. Here we report biological properties GDC-0879, a highly selective, potent, orally bioavailable small-molecule inhibitor. We used extracellular signal-regulated (ERK)-1/2 mitogen-activated protein kinase/ERK (MEK)-1/2 phosphorylation as biomarkers explore relationship between tumor outcome pharmacodynamic inhibition RAF-MEK-ERK pathway. In GDC-0879–treated mice, both cell line– patient-derived V600E tumors exhibited stronger more sustained (>90% for 8 hours) improved survival compared mutant KRAS–expressing Despite involvement activated signaling in RAS-induced tumorigenesis, decreased time progression was observed some KRAS-mutant following GDC-0879 administration. Moreover, striking differences were noted MEK across panel 130 lines. Whereas GDC-0879–mediated efficacy strictly status, also attenuated proliferation growth lines expressing wild-type (81% KRAS mutant, 38% wild type). The responsiveness cells could be dramatically altered by genetic modulation phosphatidylinositol 3-kinase pathway activity. These data suggest that GDC-0879–induced changes are dependent on point oncogenic within RAS network. Taken together, these studies increase our understanding molecular determinants antitumor resulting from have implications therapeutic intervention clinic. [Cancer Res 2009;69(7):3042–51]