Inhibition of Focal Adhesion Kinase by PF-562,271 Inhibits the Growth and Metastasis of Pancreatic Cancer Concomitant with Altering the Tumor Microenvironment
Menée in vitro et à l'aide d'un modèle murin, cette étude analyse les effets d'une petite molécule, inhibitrice de la kinase d'adhésion focale, sur la prolifération tumorale et les processus invasif et métastatique d'un adénocarcinome canalaire du pancréas
Current therapies for pancreatic ductal adenocarcinoma (PDA) target individual tumor cells. Focal adhesion kinase (FAK) is activated in PDA and levels are inversely associated with survival. We investigated the effects of PF-562,271 (a small molecule inhibitor of FAK/PYK2) on a) in vitro migration, invasion and proliferation, b) tumor proliferation, invasion and metastasis in a murine model, and c) stromal cell composition in the PDA microenvironment. Migration assays were performed to assess tumor and stromal cell migration in response to cellular factors, collagen and the effects of PF-562,271. An orthotopic murine model was used to assess the effects of PF-562,271 on tumor growth, invasion and metastasis. Proliferation assays measured PF-562,271 effects on in vitro growth. Immunohistochemistry was used to examine the effects of FAK inhibition on the cellular composition of the tumor microenvironment. FAK and PYK2 are activated and expressed in patient-derived PDA tumors, stromal components and human PDA cell lines. PF-562,271 blocked phosphorylation of FAK Y397 in a dose-dependent manner. PF-562,271 inhibited migration of tumor cells, cancer associated fibroblasts, and macrophages. Treatment of mice with PF-562,271 resulted in reduced tumor growth, invasion, and metastases. PF-562,271 had no effect on tumor necrosis, angiogenesis or apoptosis, but did decrease tumor cell proliferation and resulted in fewer tumor-associated macrophages and fibroblasts compared to control or gemcitabine. These data support a role for FAK in PDA and suggest that inhibitors of FAK may contribute to efficacious treatment of patients with PDA.
http://mct.aacrjournals.org/content/early/2011/09/08/1535-7163.MCT-11-0261.abstract