Anaplastic Lymphoma Kinase (ALK) is a potent oncogenic driver of lung adenocarcinoma (LUAD). ALK is constitutively activated by gene fusion events between the ALK and other gene fusion partners in about 2-3% of LUADs, characterized by few other gene alterations. ALK-fusions are a druggable target through potent pharmacological inhibitors of tyrosine kinase activity. Thus, several ALK-TKIs (Tyrosine Kinase Inhibitors) of first-, second- and third-generation have been developed that improved the outcomes of ALK-rearranged LUADs when used as first- or second-line agents. However, resistance mechanisms greatly limit the durability of the therapeutic effects elicited by these TKIs. The molecular mechanisms responsible for these resistance mechanisms have been in part elucidated, but overcoming acquired resistance to ALK-derived therapy remains a great challenge. Some new therapeutic strategies under investigation aim to induce long-term remission in ALK-fusion positive LUADs.

中文翻译：

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Alk 重排肺腺癌：从分子遗传学到治疗靶向。

间变性淋巴瘤激酶 (ALK) 是肺腺癌 (LUAD) 的有效致癌驱动因素。在大约 2-3% 的 LUAD 中，ALK 被 ALK 与其他基因融合伴侣之间的基因融合事件组成型激活，其特征是其他基因改变很少。ALK 融合是通过酪氨酸激酶活性的有效药理学抑制剂的药物靶标。因此，已经开发了几种第一代、第二代和第三代 ALK-TKI（酪氨酸激酶抑制剂），当用作一线或二线药物时，可改善 ALK 重排 LUAD 的结果。然而，耐药机制极大地限制了这些 TKI 产生的治疗效果的持久性。造成这些耐药机制的分子机制已部分阐明，但克服对 ALK 衍生疗法的获得性耐药仍然是一个巨大的挑战。一些正在研究的新治疗策略旨在诱导 ALK 融合阳性 LUAD 的长期缓解。