Prostate cancer cell-stromal cell crosstalk via FGFR1 mediates antitumor activity of dovitinib in bone metastases

Xinhai Wan, Paul G. Corn, Jun Yang, Nallasivam Palanisamy, Michael W. Starbuck, Eleni Efstathiou, Elsa M. Li-Ning Tapia, Amado J. Zurita, Ana Aparicio, Murali K. Ravoori, Elba S. Vazquez, Dan R. Robinson, Yi Mi Wu, Xuhong Cao, Matthew K. Iyer, Wallace McKeehan, Vikas Kundra, Fen Wang, Patricia Troncoso, Arul M. ChinnaiyanChristopher J. Logothetis, Nora M. Navone

Research output: Contribution to journalArticle

65 Scopus citations

Abstract

Bone is the most common site of prostate cancer (PCa) progression to a therapy-resistant, lethal phenotype. We found that blockade of fibroblast growth factor receptors (FGFRs) with the receptor tyrosine kinase inhibitor dovitinib has clinical activity in a subset of men with castration-resistant PCa and bone metastases. Our integrated analyses suggest that FGF signaling mediates a positive feedback loop between PCa cells and bone cells and that blockade of FGFR1 in osteoblasts partially mediates the antitumor activity of dovitinib by improving bone quality and by blocking PCa cell-bone cell interaction. These findings account for clinical observations such as reductions in lesion size and intensity on bone scans, lymph node size, and tumor-specific symptoms without proportional declines in serum prostate-specific antigen concentration. Our findings suggest that targeting FGFR has therapeutic activity in advanced PCa and provide direction for the development of therapies with FGFR inhibitors.

Original languageEnglish (US)
Article number252ra122
JournalScience translational medicine
Volume6
Issue number252
DOIs
StatePublished - Sep 3 2014

ASJC Scopus subject areas

  • Medicine(all)

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