NOVEL INSIGHTS IN ADVANCED THYROID CARCINOMA: FROM MECHANISMS TO TREATMENTS: Molecular insights into the origin, biology, and treatment of anaplastic thyroid carcinoma
Anaplastic thyroid carcinoma (ATC) is among the most daunting entities in clinical oncology. Large-scale genomic studies of thyroid cancer within the last decade have uncovered a distinct set of recurrent somatic alterations implicated in the development, aggressiveness, and treatment resistance of...
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Bioscientifica
2025-06-01
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| Series: | European Thyroid Journal |
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| author | Amir Hossein Karimi Peter YF Zeng Matthew Cecchini John W Barrett Harrison Pan Shengjie Ying Nhi Le Joe S Mymryk Laurie E Ailles Anthony C Nichols |
| author_facet | Amir Hossein Karimi Peter YF Zeng Matthew Cecchini John W Barrett Harrison Pan Shengjie Ying Nhi Le Joe S Mymryk Laurie E Ailles Anthony C Nichols |
| author_sort | Amir Hossein Karimi |
| collection | DOAJ |
| description | Anaplastic thyroid carcinoma (ATC) is among the most daunting entities in clinical oncology. Large-scale genomic studies of thyroid cancer within the last decade have uncovered a distinct set of recurrent somatic alterations implicated in the development, aggressiveness, and treatment resistance of ATC. The sequence of events leading to the development of ATC commonly begins with a tumorigenic mutation that constitutively activates the mitogen-activated protein kinase (MAPK) pathway, giving rise to indolent entities such as well-differentiated papillary or follicular thyroid carcinomas. This is followed by recurring alterations that drive oncogenic properties such as enhanced proliferation, genomic instability, replicative immortality, and dedifferentiation, culminating in the emergence of highly aggressive ATC tumors. The truncal MAPK-activating events present therapeutic opportunities, as small molecule inhibitors against key components of this pathway are available. Indeed, genotype-guided targeting of the MAPK pathway is now the standard of care for subgroups of ATC patients, and further efforts exploring additional MAPK inhibitors and the combination of immune checkpoint blockade with MAPK inhibition are overcoming resistance to the current targeted therapies in the clinic and expanding our arsenal against this disease. In this review, we summarize the current understanding of the genomic landscape of ATC, discuss the biological and clinical ramifications of recurring aberrations, and provide an overview of the opportunities and challenges in the clinical management of this lethal malignancy. |
| format | Article |
| id | doaj-art-00f74e461172432ea02ddd595089a148 |
| institution | OA Journals |
| issn | 2235-0802 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Bioscientifica |
| record_format | Article |
| series | European Thyroid Journal |
| spelling | doaj-art-00f74e461172432ea02ddd595089a1482025-08-20T02:03:31ZengBioscientificaEuropean Thyroid Journal2235-08022025-06-0114310.1530/ETJ-25-00571NOVEL INSIGHTS IN ADVANCED THYROID CARCINOMA: FROM MECHANISMS TO TREATMENTS: Molecular insights into the origin, biology, and treatment of anaplastic thyroid carcinomaAmir Hossein Karimi0Peter YF Zeng1Matthew Cecchini2John W Barrett3Harrison Pan4Shengjie Ying5Nhi Le6Joe S Mymryk7Laurie E Ailles8Anthony C Nichols9Department of Otolaryngology – Head & Neck Surgery, Western University, London, Ontario, CanadaDepartment of Otolaryngology – Head & Neck Surgery, Western University, London, Ontario, CanadaDepartment of Pathology and Laboratory Medicine, Western University, London, Ontario, CanadaDepartment of Otolaryngology – Head & Neck Surgery, Western University, London, Ontario, CanadaDepartment of Otolaryngology – Head & Neck Surgery, Western University, London, Ontario, CanadaDepartment of Otolaryngology – Head & Neck Surgery, Western University, London, Ontario, CanadaDepartment of Otolaryngology – Head & Neck Surgery, Western University, London, Ontario, CanadaDepartment of Otolaryngology – Head & Neck Surgery, Western University, London, Ontario, CanadaPrincess Margaret Cancer Centre, University Health Network, Toronto, Ontario, CanadaDepartment of Otolaryngology – Head & Neck Surgery, Western University, London, Ontario, CanadaAnaplastic thyroid carcinoma (ATC) is among the most daunting entities in clinical oncology. Large-scale genomic studies of thyroid cancer within the last decade have uncovered a distinct set of recurrent somatic alterations implicated in the development, aggressiveness, and treatment resistance of ATC. The sequence of events leading to the development of ATC commonly begins with a tumorigenic mutation that constitutively activates the mitogen-activated protein kinase (MAPK) pathway, giving rise to indolent entities such as well-differentiated papillary or follicular thyroid carcinomas. This is followed by recurring alterations that drive oncogenic properties such as enhanced proliferation, genomic instability, replicative immortality, and dedifferentiation, culminating in the emergence of highly aggressive ATC tumors. The truncal MAPK-activating events present therapeutic opportunities, as small molecule inhibitors against key components of this pathway are available. Indeed, genotype-guided targeting of the MAPK pathway is now the standard of care for subgroups of ATC patients, and further efforts exploring additional MAPK inhibitors and the combination of immune checkpoint blockade with MAPK inhibition are overcoming resistance to the current targeted therapies in the clinic and expanding our arsenal against this disease. In this review, we summarize the current understanding of the genomic landscape of ATC, discuss the biological and clinical ramifications of recurring aberrations, and provide an overview of the opportunities and challenges in the clinical management of this lethal malignancy.https://etj.bioscientifica.com/view/journals/etj/14/3/ETJ-25-0057.xmlanaplastic thyroid carcinomagenomicstargeted therapyimmunotherapy |
| spellingShingle | Amir Hossein Karimi Peter YF Zeng Matthew Cecchini John W Barrett Harrison Pan Shengjie Ying Nhi Le Joe S Mymryk Laurie E Ailles Anthony C Nichols NOVEL INSIGHTS IN ADVANCED THYROID CARCINOMA: FROM MECHANISMS TO TREATMENTS: Molecular insights into the origin, biology, and treatment of anaplastic thyroid carcinoma European Thyroid Journal anaplastic thyroid carcinoma genomics targeted therapy immunotherapy |
| title | NOVEL INSIGHTS IN ADVANCED THYROID CARCINOMA: FROM MECHANISMS TO TREATMENTS: Molecular insights into the origin, biology, and treatment of anaplastic thyroid carcinoma |
| title_full | NOVEL INSIGHTS IN ADVANCED THYROID CARCINOMA: FROM MECHANISMS TO TREATMENTS: Molecular insights into the origin, biology, and treatment of anaplastic thyroid carcinoma |
| title_fullStr | NOVEL INSIGHTS IN ADVANCED THYROID CARCINOMA: FROM MECHANISMS TO TREATMENTS: Molecular insights into the origin, biology, and treatment of anaplastic thyroid carcinoma |
| title_full_unstemmed | NOVEL INSIGHTS IN ADVANCED THYROID CARCINOMA: FROM MECHANISMS TO TREATMENTS: Molecular insights into the origin, biology, and treatment of anaplastic thyroid carcinoma |
| title_short | NOVEL INSIGHTS IN ADVANCED THYROID CARCINOMA: FROM MECHANISMS TO TREATMENTS: Molecular insights into the origin, biology, and treatment of anaplastic thyroid carcinoma |
| title_sort | novel insights in advanced thyroid carcinoma from mechanisms to treatments molecular insights into the origin biology and treatment of anaplastic thyroid carcinoma |
| topic | anaplastic thyroid carcinoma genomics targeted therapy immunotherapy |
| url | https://etj.bioscientifica.com/view/journals/etj/14/3/ETJ-25-0057.xml |
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