Characterization of oncogenic FGFR3-TACC3 fusion gene in glioblastoma

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Project Summary Fusion genes are common chromosomal aberrations in many cancers, and can be used as prognostic markers and drug targets in clinical practice. By using whole transcriptome sequencing, we and others [1, 2] have discovered FGFR3-TACC3 fusions in glioblastoma (GBM) at a recurrence rate of up to 8.3%. The fusion, caused by a tandem duplication event on 4p16.3, promoted cell proliferation in vitro and tumor progression in vivo. Overexpression of the fusion in astrocytes lead to cellular aneuploidy [1], however the mechanisms facilitating aberrant chromosomal segregation remain to be elucidated. FGFR3-TACC3 fusion positive cells exhibited higher sensitivity to the MEK inhibitor U0126 or pan FGFR inhibitor PD173074 but were more resistant to the frontline GBM chemotherapy drug, Temozolomide (TMZ). Thus, our studies have identified a novel genetic alteration in GBM that is critical for at least two major hallmarks of this deadly disease: genomic instability and resistance to chemotherapy. A recent report showed that the FGFR3-TACC3 fusion also occurs in bladder cancer [3]. Thus, the significance of this newly recognized genetic event is likely broad. We seek to further characterize this novel FGFR3-TACC3 oncogene. We hypothesize that the FGFR3-TACC3 fusion protein is a key genetic aberration that significantly modifies the signaling pathways during glioma development and progression contributing to the hallmarks of GBM. We plan to test our hypothesis by performing experiments that will determine the critical phosphorylation sites and domains within the fusion that promote tumor development, to determine the molecular mechanisms by which the fusion is resistant to temozolomide treatment, to determine the mechanisms by which the fusion promotes abnormal chromosomal segregation, and finally to determine the efficacy of current pharmacological inhibitors in treating fusion containing tumors. We will use both in vitro and in vivo approaches to answer these questions.