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 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.