Targeting Src Family Kinases Inhibits Bevacizumab-Induced Glioma Cell Invasion

Deborah Huveldt, Laura J. Lewis-Tuffin, Brett L. Carlson, Mark A. Schroeder, Fausto Rodriguez, Caterina Giannini, Evanthia Galanis, Jann N Sarkaria, Panagiotis Z Anastasiadis

Research output: Contribution to journalArticle

45 Citations (Scopus)

Abstract

Anti-VEGF antibody therapy with bevacizumab provides significant clinical benefit in patients with recurrent glioblastoma multiforme (GBM). Unfortunately, progression on bevacizumab therapy is often associated with a diffuse disease recurrence pattern, which limits subsequent therapeutic options. Therefore, there is an urgent need to understand bevacizumab's influence on glioma biology and block it's actions towards cell invasion. To explore the mechanism(s) of GBM cell invasion we have examined a panel of serially transplanted human GBM lines grown either in short-term culture, as xenografts in mouse flank, or injected orthotopically in mouse brain. Using an orthotopic xenograft model that exhibits increased invasiveness upon bevacizumab treatment, we also tested the effect of dasatinib, a broad spectrum SFK inhibitor, on bevacizumab-induced invasion. We show that 1) activation of Src family kinases (SFKs) is common in GBM, 2) the relative invasiveness of 17 serially transplanted GBM xenografts correlates strongly with p120 catenin phosphorylation at Y228, a Src kinase site, and 3) SFK activation assessed immunohistochemically in orthotopic xenografts, as well as the phosphorylation of downstream substrates occurs specifically at the invasive tumor edge. Further, we show that SFK signaling is markedly elevated at the invasive tumor front upon bevacizumab administration, and that dasatinib treatment effectively blocked the increased invasion induced by bevacizumab. Our data are consistent with the hypothesis that the increased invasiveness associated with anti-VEGF therapy is due to increased SFK signaling, and support testing the combination of dasatinib with bevacizumab in the clinic.

Original languageEnglish (US)
Article numbere56505
JournalPLoS One
Volume8
Issue number2
DOIs
StatePublished - Feb 14 2013

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cell invasion
src-Family Kinases
Glioma
phosphotransferases (kinases)
Glioblastoma
Heterografts
therapeutics
Phosphorylation
phosphorylation
Vascular Endothelial Growth Factor A
Tumors
neoplasms
Therapeutics
Chemical activation
mice
relapse
Bevacizumab
brain
Anti-Idiotypic Antibodies
Biological Sciences

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Targeting Src Family Kinases Inhibits Bevacizumab-Induced Glioma Cell Invasion. / Huveldt, Deborah; Lewis-Tuffin, Laura J.; Carlson, Brett L.; Schroeder, Mark A.; Rodriguez, Fausto; Giannini, Caterina; Galanis, Evanthia; Sarkaria, Jann N; Anastasiadis, Panagiotis Z.

In: PLoS One, Vol. 8, No. 2, e56505, 14.02.2013.

Research output: Contribution to journalArticle

Huveldt D, Lewis-Tuffin LJ, Carlson BL, Schroeder MA, Rodriguez F, Giannini C et al. Targeting Src Family Kinases Inhibits Bevacizumab-Induced Glioma Cell Invasion. PLoS One. 2013 Feb 14;8(2). e56505. https://doi.org/10.1371/journal.pone.0056505
Huveldt, Deborah ; Lewis-Tuffin, Laura J. ; Carlson, Brett L. ; Schroeder, Mark A. ; Rodriguez, Fausto ; Giannini, Caterina ; Galanis, Evanthia ; Sarkaria, Jann N ; Anastasiadis, Panagiotis Z. / Targeting Src Family Kinases Inhibits Bevacizumab-Induced Glioma Cell Invasion. In: PLoS One. 2013 ; Vol. 8, No. 2.
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