Mechanism of oncogenic signal activation by the novel fusion kinase FGFR3-BAIAP2L1
Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels la kinase issue de la fusion des gènes FGFR3 et BAIAP2L1 exerce une fonction oncogénique
Recent cancer genome profiling studies have identified many novel genetic alterations, including rearrangements of genes encoding fibroblast growth factor receptor (FGFR) family members. However, most fusion genes are not functionally characterized, and their potentials in targeted therapy are unclear. We investigated a recently discovered gene fusion between FGFR3 and BAI1-associated protein 2-like 1 (BAIAP2L1). We identified 4 bladder cancer patients and 2 lung cancer patients harboring the FGFR3-BAIAP2L1 fusion through PCR and fluorescence in situ hybridization assay screens. To investigate the oncogenic potential of the fusion gene, we established an FGFR3-BAIAP2L1 transfectant with Rat-2 fibroblast cells (Rat-2_F3-B). The FGFR3-BAIAP2L1 fusion had transforming activity in Rat2 cells, and Rat-2_F3-B cells were highly tumorigenic in mice. Rat-2_F3-B cells showed in vitro and in vivo sensitivity the selective FGFR inhibitor CH5183284/Debio 1347, indicating that FGFR3 kinase activity is critical for tumorigenesis. Gene signature analysis revealed that FGFR3-BAIAP2L1 activates growth signals, such as the mitogen-activated protein kinase pathway, and inhibits tumor-suppressive signals, such as the p53, RB1, and CDKN2A pathways. We also established Rat-2_F3-B-ΔBAR cells expressing an FGFR3-BAIAP2L1 variant lacking the Bin-Amphiphysin-Rvs (BAR) dimerization domain of BAIAP2L1, which exhibited decreased tumorigenic activity, FGFR3 phosphorylation, and F3-B-ΔBAR dimerization, compared to Rat-2_F3-B cells. Collectively, these data suggest that constitutive dimerization though the BAR domain promotes constitutive FGFR3 kinase activation and is essential for its potent oncogenic activity.
http://mct.aacrjournals.org/content/early/2015/01/14/1535-7163.MCT-14-0927-T.abstract 2015