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Updated: Jun 1, 2026
Spontaneous Murine Model of Anaplastic Thyroid Cancer
Published on: February 3, 2023
Anaplastic thyroid cancers harbor novel oncogenic mutations of the ALK gene
Avaniyapuram Kannan Murugan1, Mingzhao Xing
1Laboratory for Cellular and Molecular Thyroid Research, Division of Endocrinology and Metabolism, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
Abstract:
Thyroid cancer is the most common endocrine cancer, and targeted approaches to treat it pose considerable interest. In this study, we report the discovery of ALK gene mutations in thyroid cancer that may rationalize clinical evaluation of anaplastic lymphoma kinase (ALK) inhibitors in this setting. In undifferentiated anaplastic thyroid cancer (ATC), we identified two novel point mutations, C3592T and G3602A, in exon 23 of the ALK gene, with a prevalence of 11.11%, but found no mutations in the matched normal tissues or in well-differentiated thyroid cancers. These two mutations, resulting in L1198F and G1201E amino acid changes, respectively, both reside within the ALK tyrosine kinase domain where they dramatically increased tyrosine kinase activities. Similarly, these mutations heightened the ability of ALK to activate the phosphatidylinositol 3-kinase (PI3K)/Akt and mitogen-activated protein (MAP) kinase pathways in established mouse cells. Further investigations showed that these two ALK mutants strongly promoted cell focus formation, anchorage-independent growth, and cell invasion. Similar oncogenic properties were observed in the neuroblastoma-associated ALK mutants K1062M and F1174L but not in wild-type ALK. Overall, our results reveal two novel gain-of-function mutations of ALK in certain ATCs, and they suggest efforts to clinically evaluate the use of ALK kinase inhibitors to treat patients who harbor ATCs with these mutations.
Insights
Two novel anaplastic lymphoma kinase (ALK) gene mutations were discovered in anaplastic thyroid cancer (ATC). These ALK mutations may guide the clinical use of ALK inhibitors for treating specific thyroid cancer patients.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Thyroid cancer is the most common endocrine malignancy.
- Targeted therapies for thyroid cancer are of significant interest.
- Anaplastic thyroid cancer (ATC) is an aggressive subtype with limited treatment options.
Purpose of the Study:
- To identify genetic alterations in anaplastic thyroid cancer (ATC).
- To investigate the role of anaplastic lymphoma kinase (ALK) in thyroid cancer pathogenesis.
- To explore the potential of ALK inhibitors as a targeted therapy for ATC.
Main Methods:
- Whole exome sequencing of ATC samples.
- Identification and characterization of ALK gene mutations.
- Functional assays in mouse cell lines to assess kinase activity and oncogenic potential.
- Comparison with known ALK mutants in neuroblastoma.
Main Results:
- Two novel gain-of-function mutations (C3592T and G3602A) in the ALK gene were identified in 11.11% of ATC cases.
- These mutations led to amino acid changes (L1198F and G1201E) within the ALK tyrosine kinase domain.
- Mutated ALK demonstrated increased kinase activity, enhanced activation of PI3K/Akt and MAP kinase pathways, and promoted cell transformation and invasion.
- No mutations were found in matched normal tissues or well-differentiated thyroid cancers.
Conclusions:
- The study identified two novel oncogenic ALK mutations in anaplastic thyroid cancer.
- These findings suggest that ALK is a potential therapeutic target in a subset of ATCs.
- Clinical evaluation of anaplastic lymphoma kinase (ALK) inhibitors is warranted for patients with these specific ALK mutations.
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