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.

中文翻译：

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激酶抑制剂在甲状腺癌中的作用

甲状腺癌是最常见的内分泌恶性肿瘤，每年约占全球所有癌症病例的 3%，发病率呈上升趋势，但死亡率保持在较低水平。这种矛盾是由于颈部超声筛查发现的惰性肿瘤的过度诊断，否则这些肿瘤将保持无症状。分化型甲状腺癌 (DTC) 几乎可以治愈 95% 且预后良好。然而，这些肿瘤中有 5% 恶化为侵袭性形式：具有外渗的大肿瘤，具有区域淋巴结或远处转移，这代表了严重的临床挑战。揭示这些肿瘤的基因组图谱表明，最常见的突变发生在酪氨酸激酶受体 (RET)，在 MAPK/PI3K 信号通路（RAS 和 BRAF）或染色体重排（RET/PTC 和 NTRK 杂交体）的组分中；因此，酪氨酸激酶抑制剂 (TKI) 治疗在过去十年中出现，作为这些侵袭性肿瘤减轻 MAPK/PI3K 活化的最有效治疗选择。在这篇综述中，我们总结了恶性甲状腺癌的变体、已知有助于甲状腺细胞可塑性的分子机制和因素以及临床试验中批准的药物和正在研究的药物，概述了基因组驱动肿瘤学的可用治疗方法，最终通过针对个体基因改变定制疗法来战胜癌症的唯一机会。然而，对这些抗癌治疗的放疗和化疗耐药是常见的，并且在可能的情况下，