Awad Mark M, Shaw Alice T
Massachusetts General Hospital and Dana-Farber Cancer Institute, Boston, Massachusetts.
Harvard Medical School and Massachusetts General Hospital Cancer Center, Boston, Massachusetts.
Clin Adv Hematol Oncol. 2014 Jul;12(7):429-39.
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.
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，因克唑替尼（一种ALK、ROS1和MET酪氨酸激酶的小分子抑制剂）的研发而发生了革命性变化。然而，通过多种机制，对克唑替尼的耐药性总会出现。在过去几年中，出现了一系列新的、更有效的ALK抑制剂用于治疗ALK阳性NSCLC，包括色瑞替尼（LDK378）、阿来替尼（RO5424802/CH5424802）、AP26113、ASP3026、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。本综述重点关注这些化合物作为单一疗法或与其他药物联合使用时的药理和临床特性。鉴于有如此多的ALK抑制剂正在研发中，还讨论了如何研究以及最终如何开具这些药物的挑战。
