title: 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.affiliation: Department of Pathology and Laboratory Medicine, Department of Pharmacology and Chemical Biology, Department of Otolaryngology, Department of Surgery, Division of Endocrine Surgery, and Department of Medicine, Division of Endocrinology and Metabolism, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213.
authors.forename: Lindsey M
authors.initials: LM
authors.lastname: Kelly
authors.forename: Guillermo
authors.initials: G
authors.lastname: Barila
authors.forename: Pengyuan
authors.initials: P
authors.lastname: Liu
authors.forename: Viktoria N
authors.initials: VN
authors.lastname: Evdokimova
authors.forename: Sumita
authors.initials: S
authors.lastname: Trivedi
authors.forename: Federica
authors.initials: F
authors.lastname: Panebianco
authors.forename: Manoj
authors.initials: M
authors.lastname: Gandhi
authors.forename: Sally E
authors.initials: SE
authors.lastname: Carty
authors.forename: Steven P
authors.initials: SP
authors.lastname: Hodak
authors.forename: Jianhua
authors.initials: J
authors.lastname: Luo
authors.forename: Sanja
authors.initials: S
authors.lastname: Dacic
authors.forename: Yan P
authors.initials: YP
authors.lastname: Yu
authors.forename: Marina N
authors.initials: MN
authors.lastname: Nikiforova
authors.forename: Robert L
authors.initials: RL
authors.lastname: Ferris
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Altschuler
authors.forename: Yuri E
authors.initials: YE
authors.lastname: Nikiforov
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D001483:Base Sequence; D015153:Blotting, Western; D002148:Calmodulin-Binding Proteins / Q000235:genetics*; D000077547:Crizotinib; D050939:Gene Fusion / Q000235:genetics*; D057809:HEK293 Cells; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008565:Membrane Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000235:genetics*; D011720:Pyrazoles; D011725:Pyridines; D011743:Pyrimidines; D060888:Real-Time Polymerase Chain Reaction; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017423:Sequence Analysis, RNA; D013964:Thyroid Neoplasms / Q000235:genetics*; D059467:Transcriptome / Q000235:genetics*
chemical_list: D002148:Calmodulin-Binding Proteins; D008565:Membrane Proteins; C516714:NVP-TAE684; D009419:Nerve Tissue Proteins; D011720:Pyrazoles; D011725:Pyridines; D011743:Pyrimidines; C491925:STRN protein, human; D000077547:Crizotinib; C000626173:ALK protein, human; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases