ALK Inhibition Prolongs Survival in a Mouse Model of ALK-positive Anaplastic Thyroid Cancer

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Abstract Background Anaplastic thyroid cancer (ATC) is the most aggressive thyroid cancer with a median survival of about 6 months. So far, no therapies offering a survival benefit are established. Thus, new therapeutic approaches are urgently needed. In general, genetic alterations leading to ATC increase PI3K and MAPK/ERK signalling and include mutations in receptor tyrosine kinases and tumour suppressor genes. They often occur together with the loss of P53, the most prevalent mutation in human ATC. Among such mutations are mutations and rearrangements of the anaplastic lymphoma kinase (ALK) gene. Methods To study ATC and potential treatment options, we generated a mouse model with inducible thyrocyte-specific expression of constitutively active mutant ALK F1174L and homozygous deletion of Trp53 due to a Cre recombinase under control of the thyroglobulin promoter (Tg-Cre ERT2+/0 ;LSL-ALK F1174L/+ ;Trp53 LoxP/LoxP mice, here referred to as Trp53 KO /ALK F1174L mice). Moreover, we established several primary thyroid cancer cell lines harbouring ALK F1174L and Trp53 KO and investigated the effects of ALK inhibition in vitro and in vivo . Results Median survival of Trp53 KO /ALK F1174L mice was severely reduced and the mice showed massively enlarged thyroids. Histopathology confirmed development of locally invasive and metastatic ATC. Treatment of primary Trp53 KO /ALK F1174L ATC cells with the ALK inhibitor TAE-684 decreased AKT and ERK phosphorylation and induced a dose-dependent cytotoxicity. Trp53 KO /ALK F1174L mice treated with TAE-684 showed significantly extended median survival compared to the solvent group (66 days vs. 18 days, p < 0.0001). Conclusion Our data demonstrate that the combination of ALK F1174L mutation with Trp53 loss leads to the development of ATC. This study provides first functional data supporting the use of ALK inhibitors in patients with ALK-driven ATC. Our novel ATC mouse model and the derived cell lines offer valuable tools to explore the molecular characteristics of ATC, especially signalling pathway activation and tumour microenvironment, and to test novel therapeutics for the treatment of advanced thyroid cancers.

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