Transforming Fusions of
            <i>FGFR</i>
            and
            <i>TACC</i>
            Genes in Human Glioblastoma

Singh, Devendra Raj; Chan, Joseph M.; Zoppoli, Pietro; Niola, Francesco; Sullivan, Ryan J.; Castano, Angelica; Liu, Eric Minwei; Reichel, Jonathan; Porrati, Paola; Pellegatta, Serena; Qiu, Kunlong; Gao, Zhibo; Ceccarelli, Michele; Riccardi, Riccardo; Brat, Daniel J.; Guha, Abhijit; Aldape, Ken; Golfinos, John G.; Zagzag, David; Mikkelsen, Tom; Finocchiaro, Gaetano; Lasorella, Anna; Rabadán, Raúl; Iavarone, Antonio

doi:10.1126/science.1220834

Cited by 651 publications

(668 citation statements)

References 28 publications

(28 reference statements)

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“…However, previous studies have found the FGFR3-TACC3 fusion protein localized only to the mitotic spindle poles during mitosis, and relocated during late stage mitosis to the midbody. A mechanism for this change in recruitment and the role of FGFR3-TACC3 during interphase remains unclear (46).…”

Section: Discussionmentioning

confidence: 99%

Oncogenic Gene Fusion FGFR3-TACC3 Is Regulated by Tyrosine Phosphorylation

Nelson

Meyer

Siari

et al. 2016

Molecular Cancer Research

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Fibroblast growth factor receptors (FGFR) are critical for cell proliferation and differentiation. Mutation and/or translocation of FGFRs lead to aberrant signaling that often results in developmental syndromes or cancer growth. As sequencing of human tumors becomes more frequent, so does the detection of FGFR translocations and fusion proteins. The research conducted in this article examines a frequently identified fusion protein between FGFR3 and transforming acidic coiled-coil containing protein 3 (TACC3), frequently identified in glioblastoma, lung cancer, bladder cancer, oral cancer, head and neck squamous cell carcinoma, gallbladder cancer, and cervical cancer. Using titanium dioxide-based phosphopeptide enrichment (TiO 2 )-liquid chromatography (LC)-high mass accuracy tandem mass spectrometry (MS/MS), it was demonstrated that the fused coiled-coil TACC3 domain results in constitutive phosphorylation of key activating FGFR3 tyrosine residues. The presence of the TACC coiled-coil domain leads to increased and altered levels of FGFR3 activation, fusion protein phosphorylation, MAPK pathway activation, nuclear localization, cellular transformation, and IL3-independent proliferation. Introduction of K508R FGFR3 kinase-dead mutation abrogates these effects, except for nuclear localization which is due solely to the TACC3 domain.Implications: These results demonstrate that FGFR3 kinase activity is essential for the oncogenic effects of the FGFR3-TACC3 fusion protein and could serve as a therapeutic target, but that phosphorylated tyrosine residues within the TACC3-derived portion are not critical for activity.

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Section: Discussionmentioning

confidence: 99%

Oncogenic Gene Fusion FGFR3-TACC3 Is Regulated by Tyrosine Phosphorylation

Nelson

Meyer

Siari

et al. 2016

Molecular Cancer Research

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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

128

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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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“…In addition, this fusion protein serves as a therapeutic target for the successful drug imatinib (4). In solid human tumors, fusion genes such as the TMPRSS2-ERG fusion in prostate cancer (5), FGFR-TACC in glioblastoma (6), and DNAJB1-PRKACA in liver cancer (7) are important molecular signatures for understanding cancer mechanisms and stratifying patient groups.…”

mentioning

confidence: 99%

Recurrent BCAM-AKT2 fusion gene leads to a constitutively activated AKT2 fusion kinase in high-grade serous ovarian carcinoma

Kannan

Coarfa

Chao

et al. 2015

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

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High-grade serous ovarian cancer (HGSC) is among the most lethal forms of cancer in women. Excessive genomic rearrangements, which are expected to create fusion oncogenes, are the hallmark of this cancer. Here we report a cancer-specific gene fusion between BCAM, a membrane adhesion molecule, and AKT2, a key kinase in the PI3K signaling pathway. This fusion is present in 7% of the 60 patient cancers tested, a significant frequency considering the highly heterogeneous nature of this malignancy. Further, we provide direct evidence that BCAM-AKT2 is translated into an in-frame fusion protein in the patient's tumor. The resulting AKT2 fusion kinase is membrane-associated, constitutively phosphorylated, and activated as a functional kinase in cells. Unlike endogenous AKT2, whose activity is tightly regulated by external stimuli, BCAM-AKT2 escapes the regulation from external stimuli. Moreover, a BCAM-AKT2 fusion gene generated via chromosomal translocation using the CRISPR/Cas9 system leads to focus formation in both OVCAR8 and HEK-293T cell lines, suggesting that BCAM-AKT2 is oncogenic. Together, the results indicate that BCAM-AKT2 expression is a new mechanism of AKT2 kinase activation in HGSC. BCAM-AKT2 is the only fusion gene in HGSC that is proven to translate an aberrant yet functional kinase fusion protein with oncogenic properties. This recurrent genomic alteration is a potential therapeutic target and marker of a clinically relevant subtype for tailored therapy of HGSC.cancer-specific fusion gene | high-grade serous ovarian cancer | AKT2 | BCAM | fusion kinase O varian cancer is responsible for the death of ∼140,200 women yearly, and 70% of these deaths are due to the high-grade serous ovarian cancer (HGSC) subtype (1), which is typically detected only after it has metastasized. Genomic characterization of HGSC tumors shows that TP53 mutations are present in 96% and BRCA1/2 in 22% of HGSC (2). These mutations are thought to occur early in pathogenesis (3) and promote genomic instability, thus giving rise to the high degree of heterogeneity and genomic rearrangements that are characteristic of these cancers. The characteristic genome rearrangements in HGSC imply that recombination events such as gene fusions should be common. Moreover, if the activity of a fusion gene represents a common oncogenic mechanism, the same fusion gene is likely to occur in many patients.Recurrent fusion genes are important for understanding cancer mechanisms and developing useful clinical biomarkers and anticancer therapies. For instance, the BCR-ABL fusion gene in chronic myeloid leukemia is known to initiate oncogenesis through formation of a misregulated BCR-ABL fusion kinase. The BCR-ABL fusion gene is also a clinical biomarker of high diagnostic and prognostic utility in chronic myeloid leukemia. In addition, this fusion protein serves as a therapeutic target for the successful drug imatinib (4). In solid human tumors, fusion genes such as the TMPRSS2-ERG fusion in prostate cancer (5), FGFR-TACC in glioblastoma (6), and DNAJB1...

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Transforming Fusions of FGFR and TACC Genes in Human Glioblastoma

Cited by 651 publications

References 28 publications

Oncogenic Gene Fusion FGFR3-TACC3 Is Regulated by Tyrosine Phosphorylation

Oncogenic Gene Fusion FGFR3-TACC3 Is Regulated by Tyrosine Phosphorylation

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

Recurrent BCAM-AKT2 fusion gene leads to a constitutively activated AKT2 fusion kinase in high-grade serous ovarian carcinoma

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