Publication Date:
2012-07-28
Description:
The brain tumor glioblastoma multiforme (GBM) is among the most lethal forms of human cancer. Here, we report that a small subset of GBMs (3.1%; 3 of 97 tumors examined) harbors oncogenic chromosomal translocations that fuse in-frame the tyrosine kinase coding domains of fibroblast growth factor receptor (FGFR) genes (FGFR1 or FGFR3) to the transforming acidic coiled-coil (TACC) coding domains of TACC1 or TACC3, respectively. The FGFR-TACC fusion protein displays oncogenic activity when introduced into astrocytes or stereotactically transduced in the mouse brain. The fusion protein, which localizes to mitotic spindle poles, has constitutive kinase activity and induces mitotic and chromosomal segregation defects and triggers aneuploidy. Inhibition of FGFR kinase corrects the aneuploidy, and oral administration of an FGFR inhibitor prolongs survival of mice harboring intracranial FGFR3-TACC3-initiated glioma. FGFR-TACC fusions could potentially identify a subset of GBM patients who would benefit from targeted FGFR kinase inhibition.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3677224/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3677224/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Singh, Devendra -- Chan, Joseph Minhow -- Zoppoli, Pietro -- Niola, Francesco -- Sullivan, Ryan -- 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 -- Rabadan, Raul -- Iavarone, Antonio -- 1R01LM010140-01/LM/NLM NIH HHS/ -- R01 CA085628/CA/NCI NIH HHS/ -- R01 CA101644/CA/NCI NIH HHS/ -- R01 CA127643/CA/NCI NIH HHS/ -- R01 CA131126/CA/NCI NIH HHS/ -- R01 LM010140/LM/NLM NIH HHS/ -- R01 NS061776/NS/NINDS NIH HHS/ -- R01CA085628/CA/NCI NIH HHS/ -- R01CA101644/CA/NCI NIH HHS/ -- R01CA127643/CA/NCI NIH HHS/ -- R01CA131126/CA/NCI NIH HHS/ -- R01NS061776/NS/NINDS NIH HHS/ -- U54 CA121852/CA/NCI NIH HHS/ -- U54 CA121852-05/CA/NCI NIH HHS/ -- New York, N.Y. -- Science. 2012 Sep 7;337(6099):1231-5. doi: 10.1126/science.1220834. Epub 2012 Jul 26.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute for Cancer Genetics, Columbia University Medical Center, New York, NY, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22837387" target="_blank"〉PubMed〈/a〉
Keywords:
Aneuploidy
;
Animals
;
Antineoplastic Agents/pharmacology
;
Benzamides/pharmacology
;
Brain Neoplasms/genetics/metabolism
;
*Cell Transformation, Neoplastic
;
Chromosomal Instability
;
Enzyme Inhibitors/pharmacology
;
Fetal Proteins/chemistry/*genetics/metabolism
;
Glioblastoma/*genetics/metabolism
;
Humans
;
Mice
;
Microtubule-Associated Proteins/chemistry/*genetics/metabolism
;
Mitosis
;
Neoplasm Transplantation
;
Nuclear Proteins/chemistry/*genetics/metabolism
;
Oncogene Fusion
;
Oncogene Proteins, Fusion/chemistry/genetics/*metabolism
;
Piperazines/pharmacology
;
Protein Structure, Tertiary
;
Pyrazoles/pharmacology
;
Pyrimidines/pharmacology
;
Receptor, Fibroblast Growth Factor, Type 1/antagonists &
;
inhibitors/chemistry/*genetics/metabolism
;
Receptor, Fibroblast Growth Factor, Type 3/antagonists &
;
inhibitors/chemistry/*genetics/metabolism
;
Spindle Apparatus/metabolism
;
Translocation, Genetic
;
Xenograft Model Antitumor Assays
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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