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

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.