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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 111; no. 11; pp. 4233 - 4238
• Main Authors: Kelly, Lindsey M., Barila, Guillermo, Liu, Pengyuan, Evdokimova, Viktoria N., Trivedi, Sumita, Panebianco, Federica, Gandhi, Manoj, Carty, Sally E., Hodak, Steven P., Luo, Jianhua, Dacic, Sanja, Yu, Yan P., Nikiforova, Marina N., Ferris, Robert L., Altschuler, Daniel L., Nikiforov, Yuri E.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 18.03.2014; National Acad Sciences
• Subjects: 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; Lymphoma; 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; Thyroid cancer; Thyroid Neoplasms - genetics; Transcriptome - genetics; Tumors
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1321937111

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.