An enormous challenge of advanced cancer treatments is the development of therapeutic resistance and subsequent disease relapse. Gene fusions are key oncogenic drivers detected in advanced breast cancers that hijack integral cellular signalling pathways, resulting in gene dysregulation and ultimately contribute to treatment evasion. The FGF signalling axis is dysregulated in 5-10% of all cancers and fusions of the associated receptor proteins (FGFR1-4) are oncogenic drivers. Fortunately, FGFR - fusions are amenable to therapeutic targeting with FGFR inhibitors, and identifying further fusions in this pathway would increase the number of patients who could benefit from FGFR inhibitors.
Here, we identify and validate elevated expression of a novel FGF ligand fusion, MIR181AHG-FGF10, in drug-resistance breast cancer cells, and demonstrateits contribution to enhanced proliferative and migratory capacity. Selective inhibition of MIR181AHG-FGF10 with two FGFR inhibitors, infigratinib and pemigatinib, revealed reduction in survival and proliferative potential in clonogenic assays, reduced migration in scratch wound assays, and reduced proliferation of metastatic lung lesions from xenografts. In silico analysis of TCGA datasets identified 5 candidate FGF10 fusions in a range of malignancies. Fusions were in frame, retained FGFR activation domains, exhibited canonical dinucleotides at 5’ and 3’ fusion breakpoints and were highly expressed. Tofurther elucidate the oncogenic potential of these FGF-ligand fusions, we have generated a series of MCF7 cell lines overexpressing candidate FGF10 fusions (PAIP1-FGF10, PHC1-FGF10, NIPBL-FGF10). The identification of novel FGF fusion offers the opportunity to match FGF fusion-expressing patients with advanced cancers to FGFR inhibitors with existing FDA approval.