Abstract
Aberrant activation of fibroblast growth factor receptor (FGFR) signalling contributes to progression and metastasis of many types of cancers including breast cancer. Accordingly, FGFR targeted tyrosine kinase inhibitors (TKIs) are currently under development. However, the efficacy of FGFR TKIs in the bone microenvironment where breast cancer cells most frequently metastasize and also where FGFR is biologically active, has not been clearly investigated. We investigated the FGFR-mediated interactions among cancer and the bone microenvironment stromal cells (osteoblasts and osteoclasts), and also the effects of FGFR inhibition in bone metastasis. We showed that addition of culture supernatant from the MDA-MB-134-VI FGFR-amplified breast cancer cells-activated FGFR siganalling in osteoblasts, including increased expression of RANKL, M-CSF, and osteoprotegerin (OPG). Further in vitro analyses showed that AZD4547, an FGFR TKI currently in clinical trials for breast cancer, decreased RANKL and M-CSF, and subsequently RANKL and M-CSF-dependent osteoclastogenesis of murine bone marrow monocytes. Moreover, AZD4547 suppressed osteoclastogenesis and tumor-induced osteolysis in an orthotopic breast cancer bone metastasis mouse model using FGFR non-amplified MDA-MB-231 cells. Collectively, our results support that FGFR inhibitors inhibit the bone microenvironment stromal cells including osteoblasts and osteoclasts, and effectively suppress both tumor and stromal compartments of bone metastasis.
Highlights
Previous genomic profiling studies demonstrated that several potential target pathways are aberrantly regulated in breast cancer, including the fibroblast growth factors (FGF)/FGF receptor (FGFR) signalling pathway[1]
2 osteoblast cell lines showed similar dose-dependent sensitivities to AZD4547. These results indicate that AZD4547 inhibited the growth of osteoblastic cells and fibroblast growth factor receptor (FGFR)-amplified/overexpressing breast cancer cells
The current study was conducted to examine whether inhibition of FGFR by AZD4547 modulates the bone microenvironment, which is rich in cancer cell-derived cytokines that drive osteoclastogenesis
Summary
Previous genomic profiling studies demonstrated that several potential target pathways are aberrantly regulated in breast cancer, including the fibroblast growth factors (FGF)/FGF receptor (FGFR) signalling pathway[1]. Regulator of bone metastases and consequential morbidity in FGFR-amplified breast cancer through its biological interactions in the bone microenvironment. The interactions among FGFR-amplified breast cancer cells and other cells and factors in the bone microenvironment, including osteoblasts, osteoclasts, and the bone matrix, have not been thoroughly investigated. Because of their prominent roles in various cancers, FGFRs have become important targets for drug development[10]. Dovitinib showed antitumour activity against various cancer types with FGFR amplification and functions by altering the microenvironment through inhibition of stromal cells and through its direct cytotoxicity towards cancer cells[11,12,13,14,15]. Based on its potency and selectivity, AZD4547 is a promising agent for patients with FGFR-amplified breast cancer, for which an effective pharmacodynamics marker should be developed
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