Proceedings of the National Academy of Sciences - PNAS, 2014-03, Vol.111 (11), p.4233-4238
2014
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- Autor(en) / Beteiligte
- Titel
- Identification of the transforming STRN-ALK fusion as a potential therapeutic target in the aggressive forms of thyroid cancer
- Ist Teil von
- Proceedings of the National Academy of Sciences - PNAS, 2014-03, Vol.111 (11), p.4233-4238
- Ort / Verlag
- United States: National Academy of Sciences
- Erscheinungsjahr
- 2014
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Thyroid cancer is a common endocrine malignancy that encompasses well-differentiated as well as dedifferentiated cancer types. The latter tumors have high mortality and lack effective therapies. Using a paired-end RNA-sequencing approach, we report the discovery of rearrangements involving the anaplastic lymphoma kinase (ALK) gene in thyroid cancer. The most common of these involves a fusion between ALK and the striatin (STRN) gene, which is the result of a complex rearrangement involving the short arm of chromosome 2. STRN-ALK leads to constitutive activation of ALK kinase via dimerization mediated by the coiled-coil domain of STRN and to a kinase-dependent, thyroid-stimulating hormone-independent proliferation of thyroid cells. Moreover, expression of STRN-ALK transforms cells in vitro and induces tumor formation in nude mice. The kinase activity of STRN-ALK and the ALK-induced cell growth can be blocked by the ALK inhibitors crizotinib and TAE684. In addition to well-differentiated papillary cancer, STRN-ALK was found with a higher prevalence in poorly differentiated and anaplastic thyroid cancers, and it did not overlap with other known driver mutations in these tumors. Our data demonstrate that STRN-ALK fusion occurs in a subset of patients with highly aggressive types of thyroid cancer and provide initial evidence suggesting that it may represent a therapeutic target for these patients.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0027-8424eISSN: 1091-6490DOI: 10.1073/pnas.1321937111Titel-ID: cdi_crossref_primary_10_1073_pnas_1321937111
- Format
- –
- Schlagworte
- Antibodies, Base Sequence, Biological Sciences, Blotting, Western, Calmodulin-Binding Proteins - genetics, Cell growth, Cholangiography, Dimerization, Endocrine therapy, Gene expression, Gene fusion, Gene Fusion - genetics, Genes, HEK293 Cells, Humans, Immunohistochemistry, In Situ Hybridization, Fluorescence, Kinases, Medical treatment, Membrane Proteins - genetics, Molecular Sequence Data, Nerve Tissue Proteins - genetics, Oncology, Proteins, Pyrazoles, Pyridines, Pyrimidines, Real-Time Polymerase Chain Reaction, Receptor Protein-Tyrosine Kinases - antagonists & inhibitors, Receptor Protein-Tyrosine Kinases - genetics, Reverse Transcriptase Polymerase Chain Reaction, Rodents, Sequence Analysis, RNA, Thyroid cancer, Thyroid Neoplasms - genetics, Transcriptome - genetics, Tumors