ALK inhibitors in non-small cell lung cancer: crizotinib and beyond.
ALK inhibitors in non-small cell lung cancer: crizotinib and beyond.
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发表时间：
2014-07
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通讯作者：
M. Awad;A. Shaw
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作者：
M. Awad;A. Shaw
克唑替尼（一种酪氨酸激酶ALK、ROS 1和MET的小分子抑制剂）的开发彻底改变了伴有间变性淋巴瘤激酶（ALK）染色体重排的晚期非小细胞肺癌（NSCLC）患者的治疗。然而，对克唑替尼的耐药性总是通过多种机制产生。在过去几年中，出现了一系列用于治疗ALK阳性NSCLC的新型和更强效的ALK抑制剂，包括ceritinib（LDK 378）、alectinib（RO 5424802/CH 5424802）、AP 26113、ASP 3026、TSR-011、PF-06463922、RXDX-101、X-396和CEP-37440。携带ALK重排的癌症也可能对热休克蛋白90抑制剂治疗敏感。本文综述了这些化合物的药理学和临床特性，无论是作为单一疗法还是与其他药物联合使用。有这么多的ALK抑制剂在开发中，这些药物应该如何研究和最终规定的挑战也进行了讨论。
The treatment of patients with advanced non-small cell lung cancer (NSCLC) harboring chromosomal rearrangements of anaplastic lymphoma kinase (ALK) has been revolutionized by the development of crizotinib, a small molecule inhibitor of the tyrosine kinases ALK, ROS1, and MET. Resistance to crizotinib invariably develops, however, through a variety of mechanisms. In the last few years, a flurry of new and more potent ALK inhibitors has emerged for the treatment of ALK-positive NSCLC, including ceritinib (LDK378), alectinib (RO5424802/CH5424802), AP26113, ASP3026, TSR-011, PF-06463922, RXDX-101, X-396, and CEP-37440. Cancers harboring ALK rearrangements may also be susceptible to treatment with heat shock protein 90 inhibitors. This review focuses on the pharmacologic and clinical properties of these compounds, either as monotherapies or in combination with other drugs. With so many ALK inhibitors in development, the challenges of how these agents should be studied and ultimately prescribed are also discussed.