title: 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.
abstract: Oncogenic activation of the BRAF serine/threonine kinase has been associated with initiation and maintenance of melanoma tumors. As such, development of pharmacologic agents to target RAF proteins or their effector kinases is an area of intense investigation. Here we report the biological properties of GDC-0879, a highly selective, potent, and orally bioavailable RAF small-molecule inhibitor. We used extracellular signal-regulated kinase (ERK)-1/2 and mitogen-activated protein kinase/ERK kinase (MEK)-1/2 phosphorylation as biomarkers to explore the relationship between tumor outcome and pharmacodynamic inhibition of the RAF-MEK-ERK pathway. In GDC-0879-treated mice, both cell line- and patient-derived BRAF(V600E) tumors exhibited stronger and more sustained pharmacodynamic inhibition (>90% for 8 hours) and improved survival compared with mutant KRAS-expressing tumors. Despite the involvement of activated RAF signaling in RAS-induced tumorigenesis, decreased time to progression was observed for some KRAS-mutant tumors following GDC-0879 administration. Moreover, striking differences were noted for RAF and MEK inhibition across a panel of 130 tumor cell lines. Whereas GDC-0879-mediated efficacy was associated strictly with BRAF(V600E) status, MEK inhibition also attenuated proliferation and tumor growth of cell lines expressing wild-type BRAF (81% KRAS mutant, 38% KRAS wild type). The responsiveness of BRAF(V600E) melanoma cells to GDC-0879 could be dramatically altered by pharmacologic and genetic modulation of phosphatidylinositol 3-kinase pathway activity. These data suggest that GDC-0879-induced signaling changes are dependent on the point of oncogenic activation within the RAS network. Taken together, these studies increase our understanding of the molecular determinants for antitumor efficacy resulting from RAF pathway inhibition and have implications for therapeutic intervention in the clinic.
authors.affiliation: Department of Cancer Signaling and Translational Oncology, Genentech, Inc., South San Francisco, California 94080, USA.
authors.forename: Klaus P
authors.initials: KP
authors.lastname: Hoeflich
authors.forename: Sylvia
authors.initials: S
authors.lastname: Herter
authors.forename: Janet
authors.initials: J
authors.lastname: Tien
authors.forename: Leo
authors.initials: L
authors.lastname: Wong
authors.forename: Leanne
authors.initials: L
authors.lastname: Berry
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Chan
authors.forename: Carol
authors.initials: C
authors.lastname: O'Brien
authors.forename: Zora
authors.initials: Z
authors.lastname: Modrusan
authors.forename: Somasekar
authors.initials: S
authors.lastname: Seshagiri
authors.forename: Mark
authors.initials: M
authors.lastname: Lackner
authors.forename: Howard
authors.initials: H
authors.lastname: Stern
authors.forename: Edna
authors.initials: E
authors.lastname: Choo
authors.forename: Lesley
authors.initials: L
authors.lastname: Murray
authors.forename: Lori S
authors.initials: LS
authors.lastname: Friedman
authors.forename: Marcia
authors.initials: M
authors.lastname: Belvin
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007192:Indenes / Q000494:pharmacology*; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008545:Melanoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009154:Mutation; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics*; D011720:Pyrazoles / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: C540167:2-(4-(1-(hydroxyimino)-2,3-dihydro-1H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)ethan-1-ol; D007192:Indenes; D011720:Pyrazoles; C482128:MAP2K2 protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482125:MAP2K1 protein, human