Abstract
Fusion proteins combining FGFR and TACC are transforming in a subset of glioblastomas.
Major finding: Fusion proteins combining FGFR and TACC are transforming in a subset of glioblastomas.
Mechanism: FGFR–TACC fusions promote constitutive FGFR kinase activity and induce aneuploidy.
Impact: FGFR inhibitors may provide therapeutic benefit to patients harboring this fusion.
Defects in mitosis are thought to underlie the acquisition of chromosomal instability (CIN) and subsequent aneuploidy that are characteristic of solid tumors. One way this might occur is via chromosomal translocations that generate gain-of-function fusion proteins from genes that regulate mitosis and cell growth. Singh and colleagues investigated whether such fusions exist in human glioblastoma samples using computational approaches to analyze either whole-transcriptome or whole-exome sequencing. This analysis identified a recurrent intrachromosomal fusion of the kinase domain of fibroblast growth factor receptor (FGFR) genes FGFR1 or FGFR3 to the transforming acidic coiled-coil (TACC) domain of TACC1 or TACC3 in a small subset of glioblastomas. The resulting fusion protein was detected in primary tumor samples, and FGFR–TACC expression was sufficient to transform both fibroblasts and astrocytes in soft-agar assays in an FGFR kinase-dependent manner. Furthermore, FGFR–TACC fusions significantly enhanced the formation of highly proliferative, invasive glioma-like tumors in subcutaneous and intracranial tumor models. This oncogenic effect was mediated through constitutive FGFR kinase activity and noncanonical downstream signaling. In addition, FGFR–TACC fusions localized via the TACC domain to the mitotic spindle and the midbody, suggesting that this protein may promote chromosomal segregation errors. Indeed, expression of FGFR–TACC led to delayed, aberrant mitosis and increased aneuploidy; however, long-term FGFR–TACC expression conferred a proliferative advantage that allowed cells to overcome the growth-inhibitory effects of acute aneuploidy. Importantly, treatment with FGFR kinase inhibitors reversed the CIN and defective mitotic phenotypes in vitro and inhibited tumor growth driven by FGFR–TACC in vivo. These findings demonstrate an important role for this fusion protein in tumor initiation and suggest that FGFR inhibitors may be clinically useful in some cases of glioblastoma.
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