Abstract 4782: Inhibition of FGFR in breast cancer metastasis

Hang Lin; Saeed S. Akhand; Michael K. Wendt

doi:10.1158/1538-7445.AM2018-4782

Abstract Metastatic breast cancer is the most advanced stage of breast cancer. This type of cancer can spread other organs and cause 90% of cancer-related death. However, little is known about the molecular mechanisms which drive metastasis in breast cancer. Epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) promote tumor invasion and metastasis. Previously, it has been reported that fibroblast growth receptor 1 plays a key role during EMT: MET cycle. Therefore, optimizing FGFR inhibitors is crucial for therapeutic targeting of late-stage breast cancer. Here, we examined the efficacies of three FGFR kinase inhibitors, AZD4547, JNJ-42756493 and FIIN4, in the 4TO7 cell line both in vitro and in vivo. The 4TO7 cell line is a syngeneic model of systemic dormancy. Mammary fat pad engraftment of the 4T07 cells onto immune competent Balb/C mice results in systemic dissemination, but no macroscopic metastasis. In contrast, the 4T07 cells can escape cellular dormancy in 3D culture and form robust pulmonary tumors in mice upon tail vein inoculation. Furthermore, the 4TO7 cell line robustly responses to exogenous stimulation with FGF2. The phosphorylation of Erk1/2 downstream of FGFR was stimulated after a five-minute treatment with FGF2 and was effectively blocked with all the inhibitors tested. Furthermore, we developed a 3D culture approach that combines tumor spheroid formation in a non-adherent round bottom dish followed by placement on a bed of matrix. Our in vitro results demonstrate that both JNJ-42756493 and FIIN4 have more potent anti-proliferative activities in 3D culture and longer residence time as compared to AZD4547. In vivo, inhibition of FGFR is highly effective against 4TO7 tumors in the pulmonary microenvironment. Importantly, FIIN4 showed the least toxicity. This result suggested that covalent inhibition of FGFR is a promising cancer therapy for patients with metastatic breast cancer. Citation Format: Hang Lin, Saeed S. Akhand, Michael K. Wendt. Inhibition of FGFR in breast cancer metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4782.

Abstract 4782: Inhibition of FGFR in breast cancer metastasis

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