Title:Targeting FGFR with BGJ398 in Breast Cancer: Effect on Tumor Growth and Metastasis
Volume: 18
Issue: 10
Author(s): Ana Sahores, María May, Gonzalo R. Sequeira, Cynthia Fuentes, Britta Jacobsen, Claudia Lanari and Caroline A. Lamb*
Affiliation:
- Instituto de Biologia y Medicina Experimental (IBYME), CONICET, Buenos Aires,Argentina
Keywords:
Breast cancer, FGFR, FGFR inhibitors, BGJ398, endocrine resistance, tumor progression.
Abstract: Background: Endocrine resistance and metastatic dissemination comprise major clinical
challenges for breast cancer treatment. The fibroblast growth factor receptor family (FGFR) consists
of four tyrosine kinase transmembrane receptors, involved in key biological processes. Genomic alterations
in FGFR have been identified in advanced breast cancer and thus, FGFR are an attractive
therapeutic target. However, the efficacy of FGFR inhibitors on in vivo tumor growth is still controversial.
Objective: The purpose of this study was to evaluate the role of FGFR in tumor growth and breast
cancer progression.
Methods: Cell proliferation was assessed by 3H-thymidine uptake and cell counting in primary
cultures of endocrine resistant mammary carcinomas and a human cell line, respectively. Tumor
transplants and cell injections were used to determine in vivo growth and spontaneous metastasis.
FGFR1-3 and αSMA expression were evaluated on primary tumors by immunohistochemistry.
Results: Antiprogestin resistant murine transplants and a human xenograft express high levels of
total FGFR1-3. In vitro treatment with the FGFR inhibitor, BGJ398, impaired cell proliferation of
resistant variants versus vehicle. In vivo, versus control, BGJ398 treatment decreased one out of
four resistant tumors, however all tumors showed a decreased epithelial/stromal ratio. Finally, in a
model of hormone resistant mammary cancer that spontaneously metastasizes to the lung, BGJ398
decreased the number of mice with lung metastasis.
Conclusion: FGFR inhibitors are promising tools that require further investigation to identify sensitive
tumors. These studies suggest that targeting FGFR combined with other targeted therapies will
be useful to impair breast cancer progression.
