Identification of recurrent <i><scp>FGFR3</scp></i> fusion genes in lung cancer through kinome‐centred <scp>RNA</scp> sequencing

Majewski, Ian J.; Mittempergher, Lorenza; Davidson, N.; Bosma, Astrid; Willems, Stefan M.; Horlings, Hugo M.; Rink, Iris de; Greger, Liliana; Hooijer, Gerrit K J; Peters, Dennis; Nederlof, Petra M.; Hofland, Ingrid; Jong, Jeroen de; Wesseling, Jelle; Kluin, Roelof J.C.; Brugman, Wim; Kerkhoven, Ron; Nieboer, Frank; Roepman, Paul; Broeks, Annegien; Muley, Thomas; Jassem, Jacek; Nikliński, Jacek; Zandwijk, Nico van; Brāzma, Alvis; Oshlack, Alicia; Heuvel, Michel van den; Bernards, René

doi:10.1002/path.4209

Cited by 109 publications

(75 citation statements)

References 31 publications

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“…Although fibroblast growth factor receptor 3-transforming acidic coiled-coil-containing protein 3 (FGFR3-TACC3) fusion has been reported by Singh,19 Parker, 20 Wu, 21 and Majewski, 22 showing oncogenic potency in glioblastoma multiforme, bladder cancer, and head and neck cancer, herein, we are the first to report that FGFR3-TACC3 fusion transcripts are recurrently detected in NPC and esophageal squamous cell carcinoma (ESCC). In addition, we found that the FGFR3-TACC3 fusion gene promotes cell proliferation, colony formation, and transforming ability, indicating that FGFR3-TACC3 plays an important role in the development of NPC.…”

Section: Introductionmentioning

confidence: 99%

Recurrent FGFR3-TACC3 fusion gene in nasopharyngeal carcinoma

Li¹,

Liu²,

Lin

et al. 2014

Cancer Biology & Therapy

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These authors equally contributed to this work. Keywords: FGFR3-TACC3, fusion gene, NPC, proliferation, tumorigenesisAbbreviations: FGFR3, fibroblast growth factor receptor 3; TACC3, transforming acidic coiled-coil-containing protein 3; NPC, nasopharyngeal carcinoma; LTBR, lymphotoxin b receptor; CCND1, cyclin D1; RT-PCR, reverse transcription-PCR; FBS, fetal bovine serum; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide; SDS, sodium dodecyl sulfate; DTT, DL-dithiothreitol; DMSO, dimethyl sulfoxide; PBS, phosphate-buffered saline; PI, propidium iodide.Nasopharyngeal carcinoma (NPC) is one of the most common head and neck malignancies and exhibits regional differences in incidence. Because many fusion genes have been discovered in different types of tumors over the past few years, we aimed to investigate the existence of a fusion gene in primary NPC patients using RNA-seq. In this study, for the first time, we found that fibroblast growth factor receptor 3-transforming acidic coiled-coil-containing protein 3 (FGFR3-TACC3) fusion transcripts are recurrently detected in NPC. The presence of this fusion gene was also detected in head and neck cancer, esophageal squamous cell carcinoma (ESCC), and lung cancer. Furthermore, we found certain new isoforms of the FGFR3-TACC3 fusion transcripts, such as a gene fusion between exon 18 of FGFR3 and exon 6 or exon 14 of TACC3 and agene fusion between exon 19 of FGFR3 and exon 11 of TACC3. In addition, we showed that the FGFR3-TACC3 fusion gene promotes cell proliferation, colony formation, and transforming ability in vitro, whereas the FGFR3-TACC3 K508M mutant or treatment with the FGFR inhibitor PD173074 abrogates these effects, suggesting that FGFR3-TACC3 most likely exerts its effects through activation of FGFR kinase activity. This activation likely leads to the development of NPC. Additionally, FGFR3-TACC3 could trigger activation of the ERK and Akt signaling pathways, whereas FGFR3-TACC3 K508M mutant could not, suggesting that these 2 signaling pathways might be involved in the function of FGFR3-TACC3. Taken together, our data demonstrated the oncogenic role of FGFR3-TACC3 in vitro, indicating that FGFR3-TACC3 may be useful as a diagnostic marker and therapeutic target in cancers.

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Section: Introductionmentioning

confidence: 99%

Recurrent FGFR3-TACC3 fusion gene in nasopharyngeal carcinoma

Li¹,

Liu²,

Lin

et al. 2014

Cancer Biology & Therapy

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“…Activation of FGFR-dependent signaling pathways can stimulate tumor initiation, progression, and resistance to therapy. Translocation events implicating the FGFR1 gene and various fusions of FGFR1 are found in myeloproliferative syndromes (12); chromosomal translocations of FGFR1 or FGFR3 and the transforming acidic coiled-coil genes (TACC1 or TACC3) are oncogenic in glioblastoma multiforme, bladder cancer, head and neck cancer, and lung cancer (13)(14)(15)(16); oncogenic mutations of FGFR2 and FGFR3 are observed in lung squamous cell carcinoma; FGFR2 N549K is observed in 25% of endometrial cancers; FGFR3 t(4;14) alterations are reported in 15-20% of multiple myeloma (17)(18)(19); FGFR4 Y367C mutation in the transmembrane domain drives constitutive activation and enhanced tumorigenic phenotypes in a breast carcinoma cell line (20)(21)(22); and K535 and E550 mutants are reported to activate FGFR4 in rhabdomyosarcoma (23). FGFR amplification is reported in various cancers (24,25): FGFR1 is amplified in colorectal, lung, and renal cell cancers (26,27); FGFR2 is amplified in gastric cancer and colorectal cancer (28,29); FGFR3 is commonly amplified in bladder cancer and also is reported for cervical, oral, and hematological cancers (30)(31)(32); and FGFR4 is amplified in hepatocellular carcinoma, gastric cancer, pancreatic cancer, and ovarian cancer (33)(34)(35)(36)(37).…”

Section: Significancementioning

confidence: 99%

Development of covalent inhibitors that can overcome resistance to first-generation FGFR kinase inhibitors

Li¹,

Wang²,

Tanizaki

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

158

131

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The human FGF receptors (FGFRs) play critical roles in various human cancers, and several FGFR inhibitors are currently under clinical investigation. Resistance usually results from selection for mutant kinases that are impervious to the action of the drug or from up-regulation of compensatory signaling pathways. Preclinical studies have demonstrated that resistance to FGFR inhibitors can be acquired through mutations in the FGFR gatekeeper residue, as clinically observed for FGFR4 in embryonal rhabdomyosarcoma and neuroendocrine breast carcinomas. Here we report on the use of a structure-based drug design to develop two selective, next-generation covalent FGFR inhibitors, the FGFR irreversible inhibitors 2 (FIIN-2) and 3 (FIIN-3). To our knowledge, FIIN-2 and FIIN-3 are the first inhibitors that can potently inhibit the proliferation of cells dependent upon the gatekeeper mutants of FGFR1 or FGFR2, which confer resistance to first-generation clinical FGFR inhibitors such as NVP-BGJ398 and AZD4547. Because of the conformational flexibility of the reactive acrylamide substituent, FIIN-3 has the unprecedented ability to inhibit both the EGF receptor (EGFR) and FGFR covalently by targeting two distinct cysteine residues. We report the cocrystal structure of FGFR4 with FIIN-2, which unexpectedly exhibits a "DFG-out" covalent binding mode. The structural basis for dual FGFR and EGFR targeting by FIIN3 also is illustrated by crystal structures of FIIN-3 bound with FGFR4 V550L and EGFR L858R. These results have important implications for the design of covalent FGFR inhibitors that can overcome clinical resistance and provide the first example, to our knowledge, of a kinase inhibitor that covalently targets cysteines located in different positions within the ATP-binding pocket.drug discovery | cancer drug resistance | kinase inhibitor | structure-based drug design R eceptor tyrosine kinases (RTKs) serve as critical sensors of extracellular cues that activate a myriad of intracellular signaling pathways to regulate cell state. There are 58 receptor tyrosine kinases in the human genome, and many have been demonstrated to be constitutively activated through amplification or mutation in particular cancers. The signals emanating from these RTKs, such as epidermal growth factor receptor (EGFR), FGF receptor (FGFR), platelet-derived growth factor receptor (PDGFR), protein kinase Kit (KIT), and protein kinase c-Met (MET), have been pharmacologically proven to be essential to the survival of cancers expressing mutant forms of these proteins. However, rapid resistance to monotherapy with first-generation RTK inhibitors has been universally observed. Resistance typically arises from the emergence of cancer cells expressing mutant forms of RTKs that are impervious to the action of first-generation drugs or from the activation of by-pass signaling mechanisms. Resistance can be overcome by developing new inhibitors that target the mutant RTK directly or target bypass signaling mechanisms. Indeed this approach has been deployed succes...

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“…The initial computed tomography (CT) scan at diagnosis demonstrated wall thickening in the lesser curvature of the lower body without any evidence for distant metastasis. He received curative subtotal gastrectomy, Billroth I anastomosis, D2 dissection and the Table 1 that had been reported in the literature [7,[12][13][14][15][16][17][18][19][20][21][22][23][24]. To the best of our knowledge, FG-FR3-TACC3 fusions have not previously been described in GC.…”

Section: Case Reportmentioning

confidence: 99%

Identification of FGFR3-TACC3 gene fusion in metastatic gastric cancer

Kim

Lee

et al. 2017

Precis Future Med

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In preclinical cancer models, fibroblast growth factor receptor (FGFR) gene aberration has been known to be associated with increased tumor cell proliferation and survival in several cancer types. Oncogenic fusions consisting of FGFR3 and transforming acid coiled coil 3 (TACC3) had been identified as potential therapeutic target. We report on a gastric cancer patient with liver metastases who harbored FGFR3-TACC3 fusion which is extremely rare in gastrointestinal cancer. Herein, we report a case presentation with literature review of FGFR3-TACC3 fusion.

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Identification of recurrent FGFR3 fusion genes in lung cancer through kinome‐centred RNA sequencing

Cited by 109 publications

References 31 publications

Recurrent FGFR3-TACC3 fusion gene in nasopharyngeal carcinoma

Recurrent FGFR3-TACC3 fusion gene in nasopharyngeal carcinoma

Development of covalent inhibitors that can overcome resistance to first-generation FGFR kinase inhibitors

Identification of FGFR3-TACC3 gene fusion in metastatic gastric cancer

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