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

Abstract

Background:

Anaplastic thyroid cancer (ATC) is the most aggressive thyroid cancer with a median survival of less than six 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 signaling and include mutations in receptor tyrosine kinases and tumor suppressor genes. They often occur together with the loss of p53, the most prevalent mutation in human ATC. Among such alterations 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 (thyroglobulin [Tg]-Cre^ERT2+/0;lox-stop-lox (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 harboring 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 the 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 with the solvent group (66 days vs. 18 days, p < 0.0001).

Conclusions:

Our data demonstrate that the combination of ALK^F1174L mutation with Trp53 loss leads to the development of ATC. This study provides the 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 signaling pathway activation and tumor microenvironment, and to test novel therapeutics for the treatment of advanced thyroid cancers.