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Investigation of Requirements for Activation of Oncogenic Fusion Protein FGFR3-TACC3


Fibroblast Growth Factor Receptors (FGFRs) are receptor tyrosine kinases that regulate cellular proliferation and differentiation. When dysregulated by mutations, FGFRs can act as drivers in many types of cancers, which highlights FGFRs’ strong potential as drug targets. This work focuses on FGFR3-TACC3, an oncogenic fusion protein formed by a chromosomal translocation mutation that adds a portion of TACC3, a protein involved in mitotic spindle stabilization, to FGFR3. This fusion drives cancers by dimerizing its coiled-coil domain, from TACC3, resulting in constitutive activation of its kinase domain, from FGFR3, which subsequently activates downstream MAPK and Akt signaling pathways. In addition, the oncogenicity of FGFR3-TACC3 was shown to depend on either entrance to the secretory pathway or plasma membrane localization. Although tyrosine kinase inhibitors are used to treat dysregulated FGFR driven cancers, acquired resistance is often observed in patients. This suggests the need for new approaches to treat these diseases, including potentially targeting the dimerization partner instead of kinase activity of oncogenic fusions. Identified in patients with different breakpoints, FGFR3-TACC3 was found with varying lengths of TACC3. Initially, two breakpoints were shown to exhibit significantly different levels of oncogenic potential, determined by their abilities to transform NIH3T3 cells. This led to the analysis of a selection of breakpoints to determine the minimum requirements of TACC3 for activation of FGFR3-TACC3. In contrast with all other breakpoints, the shortest breakpoint FGFR3-TACC3 exon 14, despite being identified in a head and neck squamous cell carcinoma, was shown to be unable to activate downstream signaling pathways nor exhibit transforming ability. With the addition of one more exon, FGFR3-TACC3 exon 13 was shown to be the shortest identified breakpoint to retain both downstream signaling and transforming ability. A cysteine residue, that is present in TACC3 of all breakpoints, was shown to form disulfide-bonded dimers only in fusions that exhibit downstream signaling and transforming ability. To determine the minimum number of heptad repeats of coiled-coil required for dimerization and subsequent activation of the fusion, individual heptad repeats were incrementally deleted from FGFR3-TACC3 exon 13 breakpoint to assess changes in transforming ability. Preliminary data suggests that all eight heptads present in TACC3 exon 13 are required for activation of FGFR3-TACC3.

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