title: Oncogenic RAS pathway activation promotes resistance to anti-VEGF therapy through G-CSF-induced neutrophil recruitment.
abstract: Granulocyte-colony stimulating factor (G-CSF) promotes mobilization of CD11b(+)Gr1(+) myeloid cells and has been implicated in resistance to anti-VEGF therapy in mouse models. High G-CSF production has been associated with a poor prognosis in cancer patients. Here we show that activation of the RAS/MEK/ERK pathway regulates G-CSF expression through the Ets transcription factor. Several growth factors induced G-CSF expression by a MEK-dependent mechanism. Inhibition of G-CSF release with a MEK inhibitor markedly reduced G-CSF production in vitro and synergized with anti-VEGF antibodies to reduce CD11b(+)Ly6G(+) neutrophil mobilization and tumor growth and led to increased survival in animal models of cancer, including a genetically engineered mouse model of pancreatic adenocarcinoma. Analysis of biopsies from pancreatic cancer patients revealed increased phospho-MEK, G-CSF, and Ets expression and enhanced neutrophil recruitment compared with normal pancreata. These results provide insights into G-CSF regulation and on the mechanism of action of MEK inhibitors and point to unique anticancer strategies.
authors.affiliation: Genentech, Inc., South San Francisco, CA 94080, USA.
authors.forename: Vernon T
authors.initials: VT
authors.lastname: Phan
authors.forename: Xiumin
authors.initials: X
authors.lastname: Wu
authors.forename: Jason H
authors.initials: JH
authors.lastname: Cheng
authors.forename: Rebecca X
authors.initials: RX
authors.lastname: Sheng
authors.forename: Alicia S
authors.initials: AS
authors.lastname: Chung
authors.forename: Guanglei
authors.initials: G
authors.lastname: Zhuang
authors.forename: Christopher
authors.initials: C
authors.lastname: Tran
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Song
authors.forename: Marcin
authors.initials: M
authors.lastname: Kowanetz
authors.forename: Amy
authors.initials: A
authors.lastname: Sambrone
authors.forename: Martha
authors.initials: M
authors.lastname: Tan
authors.forename: Y Gloria
authors.initials: YG
authors.lastname: Meng
authors.forename: Erica L
authors.initials: EL
authors.lastname: Jackson
authors.forename: Franklin V
authors.initials: FV
authors.lastname: Peale
authors.forename: Melissa R
authors.initials: MR
authors.lastname: Junttila
authors.forename: Napoleone
authors.initials: N
authors.lastname: Ferrara
mesh_terms: D000818:Animals; D001665:Binding Sites; D045744:Cell Line, Tumor; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism*; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D009369:Neoplasms / Q000378:metabolism; D009389:Neovascularization, Pathologic; D020556:Neutrophil Infiltration; D009504:Neutrophils / Q000166:cytology*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D050787:Proto-Oncogene Protein c-ets-2 / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000627:therapeutic use*
chemical_list: C494069:ETS2 protein, human; D050787:Proto-Oncogene Protein c-ets-2; D042461:Vascular Endothelial Growth Factor A; D016179:Granulocyte Colony-Stimulating Factor; D011505:Protein-Tyrosine Kinases