Targeting FGFR/PDGFR/VEGFR impairs tumor growth, angiogenesis and metastasis by effects on tumor cells, endothelial cells and pericytes in pancreatic cancer
Menée in vitro et à l'aide d'un modèle murin, cette étude évalue les perspectives offertes par un composé appelé TKI258, un inhibiteur de trois récepteurs à activité tyrosine kinase (FGFR, PDGFR et VEGFR), pour le traitement du cancer du pancréas
Activation of receptor tyrosine kinases (RTKs) such as fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptor (PDGFR) and vascular-endothelial growth factor receptor (VEGFR) have been implicated in tumor progression and metastasis in human pancreatic cancer. In this study we investigated the effects of TKI258, a tyrosine kinase inhibitor to FGFR, PDGFR and VEGFR on pancreatic cancer cell lines (HPAF-II, BxPC-3, MiaPaCa-2, L3.6pl), endothelial cells (ECs) and vascular smooth muscle cells (VSMCs). Results showed that treatment with TKI258 impaired activation of signaling intermediates in pancreatic cancer cells, ECs and VSMCs, even upon stimulation with FGF-1, FGF-2, VEGF-A and PDGF-B. Furthermore, blockade of FGFR/PDGFR/VEGFR reduced survivin expression and improved activity of Gemcitabine in MiaPaCa2 pancreatic cancer cells. In addition, motility of cancer cells, ECs and VSMCs was reduced upon treatment with TKI258. In vivo, therapy with TKI258 led to dose-dependent inhibition of subcutaneous (HPAF-II) and orthotopic (L3.6pl) tumor growth. Immunohistochemical analysis revealed effects on tumor cell proliferation (BrdU) and tumor vascularisation (CD31). Moreover, lymph node metastases were significantly reduced in the orthotopic tumor model when treatment was initiated early with TKI258 (30 mg/kg/d). In established tumors, TKI258 (30 mg/kg/d) led to significant growth delay and improved survival in subcutaneous and orthotopic models, respectively. These data provide evidence that targeting FGFR/PDFGR/VEGFR with TKI258 may be effective in human pancreatic cancer and warrants further clinical evaluation.
http://mct.aacrjournals.org/content/early/2011/08/31/1535-7163.MCT-11-0312.abstract