An enormous challenge of advanced cancer treatment is the development of therapeutic resistance and subsequent disease relapse. Gene fusions are key oncogenic drivers detected in advanced cancers that can hijack integral cellular signalling pathways, resulting in gene dysregulation and ultimately contribute to treatment evasion. The FGF (fibroblast growth factor) 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 these are used to identify patients for treatment. The identification of further fusions in this pathway would increase the number of patients that could benefit from FGFR inhibitors.
Here, we identify and validate elevated expression of a novel FGF ligand fusion, MIR181AHG-FGF10 in drug resistant breast cancer cells, and demonstrate its 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, maintained FGFR activation domains, exhibited canonical dinucleotides at 5’ and 3’ fusion breakpoints and were highly expressed. The identification of novel FGF fusions therefore presents the opportunity to match FGF fusion-expressing patients with advanced cancers to FGFR inhibitors with existing FDA approval.