Identification of the transforming STRN-ALK fusion as a potential therapeutic target in the aggressive forms of thyroid cancer.

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.

• Authors: Lindsey M Kelly, Guillermo Barila, Pengyuan Liu, Viktoria N Evdokimova, Sumita Trivedi, Federica Panebianco, Manoj Gandhi, Sally E Carty, Steven P Hodak, Jianhua Luo, Sanja Dacic, Yan P Yu, Marina N Nikiforova, Robert L Ferris, Daniel L Altschuler, Yuri E Nikiforov
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 111 Issue 11 Pg. 4233-8 (Mar 18 2014) ISSN: 1091-6490 [Electronic] United States
• PMID: 24613930 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Calmodulin-Binding Proteins
• Membrane Proteins
• NVP-TAE684
• Nerve Tissue Proteins
• Pyrazoles
• Pyridines
• Pyrimidines
• STRN protein, human
• Crizotinib
• ALK protein, human
• Alk protein, mouse
• Anaplastic Lymphoma Kinase
• Receptor Protein-Tyrosine Kinases

Topics

• Anaplastic Lymphoma Kinase
• Base Sequence
• Blotting, Western
• Calmodulin-Binding Proteins (genetics)
• Crizotinib
• Gene Fusion (genetics)
• HEK293 Cells
• Humans
• Immunohistochemistry
• In Situ Hybridization, Fluorescence
• Membrane Proteins (genetics)
• Molecular Sequence Data
• Nerve Tissue Proteins (genetics)
• Pyrazoles
• Pyridines
• Pyrimidines
• Real-Time Polymerase Chain Reaction
• Receptor Protein-Tyrosine Kinases (antagonists & inhibitors, genetics)
• Reverse Transcriptase Polymerase Chain Reaction
• Sequence Analysis, RNA
• Thyroid Neoplasms (genetics)
• Transcriptome (genetics)