title: Targeting Src family kinases inhibits bevacizumab-induced glioma cell invasion.
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.
authors: Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida, United States of America.
authors: Deborah
authors: D
authors: Huveldt
authors: Laura J
authors: LJ
authors: Lewis-Tuffin
authors: Brett L
authors: BL
authors: Carlson
authors: Mark A
authors: MA
authors: Schroeder
authors: Fausto
authors: F
authors: Rodriguez
authors: Caterina
authors: C
authors: Giannini
authors: Evanthia
authors: E
authors: Galanis
authors: Jann N
authors: JN
authors: Sarkaria
authors: Panos Z
authors: PZ
authors: Anastasiadis
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D000068258:Bevacizumab; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D000069439:Dasatinib; D004789:Enzyme Activation / Q000187:drug effects; D005910:Glioma / Q000473:pathology*; D006801:Humans; D051379:Mice; D058990:Molecular Targeted Therapy; D009361:Neoplasm Invasiveness; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013844:Thiazoles / Q000494:pharmacology; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D000068258:Bevacizumab; D019061:src-Family Kinases; D000069439:Dasatinib