Thyroid cancer is the most common endocrine malignancy, accounting for about 3% of all cancer cases each year worldwide with increasing incidence, but with the mortality remaining stable at low levels. This contradiction is due to overdiagnosis of indolent neoplasms identified by neck ultrasound screening that would remain otherwise asymptomatic. Differentiated thyroid carcinomas (DTCs) are almost curable for 95% with a good prognosis. However, 5% of these tumours worsened toward aggressive forms: large tumours with extravasal invasion, either with regional lymph node or distant metastasis, that represent a serious clinical challenge. The unveiling of the genomic landscape of these tumours shows that the most frequent mutations occur in tyrosine kinase receptors (RET), in components of the MAPK/PI3K signalling pathway (RAS and BRAF) or chromosomal rearrangements (RET/PTC and NTRK hybrids); thus, tyrosine-kinase inhibitor (TKI) treatments arose in the last decade as the most effective therapeutic option for these aggressive tumours to mitigate the MAPK/PI3K activation. In this review, we summarize the variants of malignant thyroid cancers, the molecular mechanisms and factors known to contribute to thyroid cell plasticity and the approved drugs in the clinical trials and those under investigation, providing an overview of available treatments toward a genome-driven oncology, the only opportunity to beat cancer eventually through tailoring the therapy to individual genetic alterations. However, radiotherapeutic and chemotherapeutic resistances to these anticancer treatments are common and, wherever possible, we discuss these issues.
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