Targeting multiple tyrosine kinase receptors with Dovitinib blocks invasion and the interaction between tumor cells and cancer-associated fibroblasts in breast cancer

Abstract

A constitutive and dynamic interaction between tumor cells and their surrounding stroma is a prerequisite for tumor invasion and metastasis. Fibroblasts and myofibroblasts (collectively called cancer associated fibroblasts, CAFs) often represent the major cellular components of tumor stroma. Tumor cells secret different growth factors which induce CAFs proliferation and differentiation, and, consequently, CAFs secrete different chemokines, cytokines or growth factors which induce tumor cell invasion and metastasis. In this study we showed here that CAFs from breast cancer surgical specimens significantly induced the invasion of breast cancer cells in vitro. Most interestingly, the novel multiple tyrosine kinase inhibitor Dovitinib significantly blocked the CAFs-induced invasion of breast cancer cells by, at least in part, inhibition of the expression and secretion of CCL2, CCL5 and VEGF in CAFs. Inhibition of PI3K/Akt/mTOR signaling could be responsible for the effects of Dovitinib, since Dovitinib antagonized the promoted phosphorylated Akt after treatment with PDGF, FGF or breast cancer cell-conditioned media. Treatment with Dovitinib in combination with PI3K/Akt/mTOR signaling inhibitors Ly294002 or RAD001 resulted in additive inhibition of cell invasion. This is the first in vitro study to show that the multiple tyrosine kinase inhibitor has therapeutic activities against breast cancer metastasis by targeting both tumor cells and CAFs.

Effects of FGFR inhibitors TKI258, BGJ398 and AZD4547 on breast cancer cells in 2D, 3D and tissue explant cultures

“…The selective FGFRis BGJ398 and AZD4547 had no effect on migration, but they inhibited invasion of the cells, suggesting that invasion but not migration was dependent on FGFR-mediated mechanisms in these cells. Our observations are in line with the results of Zang et al, who have previously reported TKI258 inhibition of invasion of MDA-MB-231 cells, although they did not study ERK1/2 phosphorylation [ 31 ].…”

The FGF/FGFR System in Breast Cancer: Oncogenic Features and Therapeutic Perspectives

“…Besides this, the release of FGF7 by CAFs and its interaction with the cognate receptor FGFR2 have been shown to induce ER phosphorylation, ubiquitination, and subsequent proteasomal degradation, therefore counteracting the endocrine treatment in breast cancer cells [ 83 ]. Besides this, the FGF/FGFR axis has been involved in a feedforward stimulatory loop coupling CAFs to breast cancer cells [ 97 , 98 ], whereas the PDGF released by breast tumor cells stimulated the production of FGFs by CAFs towards the activation of proliferative and pro-metastatic pathways in breast cancer cells [ 97 ]. Likewise, the Hedgehog ligand produced by TNBC cells prompted the release of FGF5 by CAFs, leading to the acquisition of a chemo-resistant and cancer stem cell phenotype [ 99 ].…”

Tyrosine Phosphorylation as a Widespread Regulatory Mechanism in Prokaryotes

“…Critically, dysregulated kinase activity is associated with many diseases, including cancer, and for that reason kinases are widely recognized as being "druggable" targets for cancer treatments. In fact, over 20 tyrosine kinase inhibitor drugs, mostly large antibody complexes, are approved for clinical use, and many more are in the development pipeline (71,72). Coincidently, phosphorylation studies are continually being pursued to investigate aggressive human cancers (38,(73)(74)(75)(76), with a goal of improved health care outcomes and novel kinase inhibitor therapies.…”