The STRN–ALK fusion gene promotes thyroid cell transformation and dependency on ALK signaling.

  • Major finding: The STRN–ALK fusion gene promotes thyroid cell transformation and dependency on ALK signaling.

  • Clinical relevance: Cells that express the STRN–ALK fusion gene are sensitive to ALK kinase inhibitors.

  • Impact:STRNALK fusions are recurrent in dedifferentiated thyroid cancers and may be exploited therapeutically.

Most thyroid cancers can be treated with surgery and radioactive iodine, but most poorly differentiated and anaplastic thyroid cancers and some well-differentiated tumors are aggressive and associated with poorer survival. Kelly and colleagues performed whole-transcriptome RNA sequencing to identify thyroid cancer-specific gene fusions that might suggest potential therapeutic targets in tumors lacking known driver mutations. Three of 21 well-differentiated papillary thyroid tumors (PTC) analyzed were found to harbor fusions that involved anaplastic lymphoma kinase (ALK): One tumor contained the oncogenic fusion EML4–ALK previously described in lung cancer, and the remaining two tumors harbored fusions of the caveolin-binding and coiled-coil domains of striatin (STRN), which encodes a calcium-dependent calmodulin-binding protein, to the intracellular juxtamembrane and tyrosine kinase domains of ALK. Sequencing of additional thyroid tumors identified ALK fusions in a total of 1.6% of PTCs, 9% of poorly differentiated thyroid cancers, and 4% of anaplastic thyroid cancers, indicating that STRN–ALK fusions are significantly enriched in aggressive thyroid cancers prone to dedifferentiation. Tumors harboring STRN–ALK displayed elevated expression, constitutive kinase activation, and diffuse cytoplasmic localization of ALK, and mutational analysis revealed that the STRN coiled-coiled domain is required for ALK hyperactivation due to its role in facilitating fusion protein dimerization and ligand-independent activation, suggesting that the fusions have functional relevance in thyroid cancer. Indeed, expression of the STRN–ALK fusion protein, but not a kinase-dead mutant, induced thyroid cell proliferation and tumor formation in vitro and in vivo. Importantly, treatment with the clinically available ALK inhibitors crizotinib and TAE684 reduced STRN–ALK kinase activity in vitro and inhibited the proliferation of cells expressing the STRN–ALK fusion protein. Together, these results implicate ALK fusion genes as drivers of thyroid cancer that may be exploited therapeutically.

Kelly LM, Barila G, Liu P, Evdokimova VN, Trivedi S, Panebianco F, et al. Identification of the transforming STRN-ALK fusion as a potential therapeutic target in aggressive forms of thyroid cancer. Proc Natl Acad Sci U S A 2014 Feb 3 [Epub ahead of print].