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Mol Cancer Res. 2019 Jul 2. pii: molcanres.0415.2019. doi: 10.1158/1541-7786.MCR-19-0415. [Epub ahead of print]

A Novel FGFR3 Splice Variant Preferentially Expressed in African American Prostate Cancer Drives Aggressive Phenotypes and Docetaxel Resistance.

Author information

1
Pharmacology and Physiology, George Washington University.
2
University of Maryland Eastern Shore.
3
Epidemiology Department, University of Hawaii Cancer Center.
4
University of Michigan-Ann Arbor.
5
Cartilage Biology and Orthopaedics Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health.
6
Biochemistry and Molecular Medicine, George Washington University.
7
Department of Pathology, The George Washington University School of Medicine and Health Sciences.
8
Pharmacology, George Washington University.
9
Surgery, Center for Prostate Disease Research.
10
Department of Pharmacology & Physiology, George Washington University School of Medicine nhlee@gwu.edu.

Abstract

Alternative splicing (AS) has been shown to participate in prostate cancer (PCa) development and progression; however, a link between AS and PCa health disparities has been largely unexplored. Here we report on the cloning of a novel splice variant of FGFR3 that is preferentially expressed in African American (AA) PCa. This novel variant (FGFR3-S) omits exon 14, comprising 123 nucleotides that encode the activation loop in the intracellular split kinase domain. Ectopic overexpression of FGFR3-S in European American (EA) PCa cell lines (PC-3 and LNCaP) led to enhanced receptor autophosphorylation and increased activation of the downstream signaling effectors AKT, STAT3, and ribosomal S6 compared to FGFR3-L (retains exon 14). The increased oncogenic signaling imparted by FGFR3-S was associated with a substantial gain in proliferative and anti-apoptotic activities, as well as a modest but significant gain in cell motility. Moreover, the FGFR3-S-conferred proliferative and motility gains were highly resistant to the pan-FGFR small molecule inhibitor dovitinib and the anti-apoptotic gain was insensitive to the cytotoxic drug docetaxel, which stands in marked contrast to dovitinib- and docetaxal-sensitive FGFR3-L. In an in vivo xenograft model, mice injected with PC-3 cells overexpressing FGFR3-S exhibited significantly increased tumor growth and resistance to dovitinib treatment compared to cells overexpressing FGFR3-L. In agreement with our in vitro and in vivo findings, a high FGFR3-S/FGFR3-L expression ratio in PCa specimens was associated with poor patient prognosis. Implications: This work identifies a novel FGFR3 splice variant and supports the hypothesis that differential AS participates in PCa health disparities.

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