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

Phan VT,Wu X,Cheng JH,Sheng RX,Chung AS,Zhuang G,Tran C,Song Q,Kowanetz M,Sambrone A,Tan M,Meng YG,Jackson EL,Peale FV,Junttila MR,Ferrara N

doi

10.1073/pnas.1303302110

subject

Has Abstract

pub_date

2013-04-09 00:00:00

pages

6079-84

issue

15

eissn

0027-8424

issn

1091-6490

pii

1303302110

journal_volume

110

pub_type

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