FGFR Inhibitor AZD4547 Disrupts Inflammatory CAF Crosstalk With Cancer Cells and Macrophages and Attenuates Metastasis in Pancreatic Cancer.

Cancer-associated fibroblasts (CAFs) are key cell types within the tumor microenvironment (TME), responsible for their pro-tumorigenic effects and metastasis. Specifically, inflammatory CAFs (iCAFs), a CAF subtype, are known to induce tumor cell progression, migration, and immunosuppression. Fibroblast growth factor receptors (FGFRs) play a crucial role in cell differentiation, migration, and proliferation. In this study, we investigated the effect of FGFR kinase inhibitor AZD4547 (AZD), a clinical-stage drug, on iCAF differentiation and iCAF-mediated effects on the tumor-stroma interaction in vitro and in vivo. Treatment with AZD inhibited the differentiation of human pancreatic stellate cells into iCAFs using IL-1α, as shown with reduced IL-6 expression. FGFR1, 2, 3, and 4 were upregulated in iCAFs, which were inhibited by AZD. Treatment with AZD also attenuated the iCAF-mediated paracrine effect on the PDAC cell-induced migration and epithelial-mesenchymal transition of tumor cells, as well as polarization of macrophages towards the M1 phenotype in vitro. Furthermore, AZD significantly reduced the growth of tumor cells and fibroblasts in co-cultured 3D heterospheroids in vitro. In vivo, treatment with AZD attenuated the tumor growth in the syngeneic subcutaneous KPC murine tumor model. Interestingly, flow cytometry and immunofluorescent staining analyses on isolated tumors revealed that AZD-treated tumors had a reduced iCAF population and M2-type macrophages. Furthermore, we found that AZD treatment reduced the liver metastasis, as shown with the reduction of ki-67 and p53 tumor markers in the AZD-treated group compared to the vehicle group. Altogether, this study demonstrates that FGFRs are overexpressed on iCAFs and their inhibition using AZD diminishes iCAF-mediated paracrine signaling with tumor cells and macrophages, thereby attenuating tumor growth and metastasis.