UC San Diego

Fibroblast Growth Factor Receptors (FGFRs) are critical for cell proliferation and differentiation. Mutation and/or translocation of FGFRs lead to aberrant signaling that often results in developmental syndromes or cancer growth. As sequencing of human tumors becomes more frequent, so does the emergence of FGFR translocations and fusion proteins. The research conducted in this work will focus on a frequently identified fusion protein between FGFR3 and transforming acidic coiled-coil containing protein 3 (TACC3). As detailed in this dissertation, it is apparent that the fused coiled-coil TACC3 domain results in constitutive phosphorylation of key activating FGFR3 tyrosine residues. The presence of the TACC coiled-coil domain leads to increased and altered levels of FGFR3 activation, fusion protein phosphorylation, MAPK pathway activation, nuclear localization, cellular transformation, and IL3-independent proliferation. Introduction of K508R FGFR3 kinase dead mutation abrogates these effects, except for nuclear localization which is due solely to the TACC3 domain. We further demonstrate that the oncogenic effects initiated by FGFR3-TACC3 are dependent on the overactivation of the MAPK pathway and localization of FGFR3-TACC3 to the secretory pathway or the plasma membrane. The activation of the MAPK pathway is essential for cell transformation but involvement in the cell cycle via the canonical TACC3 pathways is not. Additionally, we have shown that kinase inhibitors for MEK (Trametinib) and FGFR (BGJ398) are effective in blocking cell transformation and MAPK pathway upregulation. The need for precision medicine is evidenced by the different effects these inhibitors have against various FGFR3-TACC3 breakpoints. The existence of FGFR3-TACC3 fusions in human cancers creates additional challenges and opportunities for identifying effective treatment strategies. The development of such personalized medicines will be essential in treating patients who harbor oncogenic drivers such as FGFR3-TACC3.