title: Mechanism of Oncogenic Signal Activation by the Novel Fusion Kinase FGFR3-BAIAP2L1.
abstract: Recent cancer genome profiling studies have identified many novel genetic alterations, including rearrangements of genes encoding 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 patients with bladder cancer and 2 patients with lung cancer harboring the FGFR3-BAIAP2L1 fusion through PCR and FISH 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 in 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 MAPK 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 with Rat-2_F3-B cells. Collectively, these data suggest that constitutive dimerization through the BAR domain promotes constitutive FGFR3 kinase activation and is essential for its potent oncogenic activity.
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa, Japan. nakanishiyst@chugai-pharm.co.jp.
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Nakanishi
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa, Japan.
authors.forename: Nukinori
authors.initials: N
authors.lastname: Akiyama
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Tsukaguchi
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa, Japan.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Fujii
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa, Japan.
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Satoh
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa, Japan.
authors.forename: Nobuya
authors.initials: N
authors.lastname: Ishii
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Aoki
mesh_terms: D016475:3T3 Cells; D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D005347:Fibroblasts / Q000378:metabolism; D045325:HCT116 Cells; D057809:HEK293 Cells; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics; D051379:Mice; D008840:Microfilament Proteins / Q000235:genetics*; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D010766:Phosphorylation / Q000235:genetics; D051381:Rats; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics*; D001749:Urinary Bladder Neoplasms / Q000235:genetics
chemical_list: C523100:BAIAP2L1 protein, human; D008840:Microfilament Proteins; D015514:Oncogene Proteins, Fusion; D051498:Receptor, Fibroblast Growth Factor, Type 3; D020928:Mitogen-Activated Protein Kinases