PRECLINICAL STUDY Inhibition of FGFR signaling by PD173074 improves antitumor immunity and impairs breast cancer metastasis

Abstract Aberrant fibroblast growth factor (FGF) and FGF receptor (FGFR) system have been associated with breast cancer. The objectives of our study were to inves-tigate the effects and mechanisms of FGFR inhibition on tumor growth and metastasis on breast cancer. Our studies showed that the FGFR inhibitor PD173074 decreased the viability of several human breast cancer cells, as well as 4T1 murine mammary tumor cells. Therefore, we chose 4T1 cells to study PD173074’s antitumor mechanism. Flow cytometry showed that PD173074 induced 4T1 cell apop-tosis in a concentration-dependent manner. Western blot demonstrated that PD173074-induced apoptosis was cor-related with the inhibition of Mcl-1 and survivin. More-over, PD173074 also significantly increased the ratio of Bax/Bcl-2. PD173074 could also block 4T1 cell migration and invasion in vitro. In 4T1 tumor-bearing mice, PD173074 significantly inhibited tumor growth without obvious side effects. Meanwhile, PD173074 functionally reduced microvessel density and proliferation index and induced tumor apoptosis. Importantly, we found that FGFR inhibition by PD173074 reduced myeloid-derived sup-pressor cells (MDSCs) in the blood, spleens and tumors, accompanied by the increased infiltration of CD4? and CD8? T cells in the spleens and tumors. Furthermore, PD173074 significantly inhibited breast tumor metastasis to the lung of inoculated 4T1 breast cancer cells, which was accompanied by a reduction in MDSCs. Our findings suggested that FGFR inhibition could delay breast tumor progression, impair lung metastasis and break immuno-suppression by effecting on tumor microenvironment, which may provide a promising therapeutic approach for breast cancer patient