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Identification of the transforming STRN-ALK fusion as a potential therapeutic target in the aggressive forms of thyroid cancer. Proc Natl Acad Sci U S A 2014 Mar 18;111(11):4233-8

Date

03/13/2014

Pubmed ID

24613930

Pubmed Central ID

PMC3964116

DOI

10.1073/pnas.1321937111

Scopus ID

2-s2.0-84896531092   144 Citations

Abstract

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.

Author List

Kelly LM, Barila G, Liu P, Evdokimova VN, Trivedi S, Panebianco F, Gandhi M, Carty SE, Hodak SP, Luo J, Dacic S, Yu YP, Nikiforova MN, Ferris RL, Altschuler DL, Nikiforov YE

Author

Pengyuan Liu PhD Adjunct Professor in the Physiology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Base Sequence
Blotting, Western
Calmodulin-Binding Proteins
Gene Fusion
HEK293 Cells
Humans
Immunohistochemistry
In Situ Hybridization, Fluorescence
Membrane Proteins
Molecular Sequence Data
Nerve Tissue Proteins
Pyrazoles
Pyridines
Pyrimidines
Real-Time Polymerase Chain Reaction
Receptor Protein-Tyrosine Kinases
Reverse Transcriptase Polymerase Chain Reaction
Sequence Analysis, RNA
Thyroid Neoplasms
Transcriptome
jenkins-FCD Prod-484 8aa07fc50b7f6d102f3dda2f4c7056ff84294d1d