Centre de Recherche en Oncologie Expérimentale, Institut de Recherche Pierre Fabre, Toulouse, Cedex 4, France.
Expert Opin Ther Targets. 2012 Nov;16(11):1127-38. doi: 10.1517/14728222.2012.719498. Epub 2012 Sep 24.
Anaplastic lymphoma kinase (ALK), a tyrosine kinase receptor, has been initially identified through its involvement in chromosomal translocations associated with anaplastic large cell lymphoma. However, recent evidence that aberrant ALK activity is also involved in an expanding number of tumor types, such as other lymphomas, inflammatory myofibroblastic tumor, neuroblastomas and some carcinomas, including non-small cell lung carcinomas, is boosting research progress in ALK-targeted therapies.
The first aim of this review is to describe current understandings about the ALK tyrosine kinase and its implication in the oncogenesis of human cancers as a fusion protein or through mutations. The second goal is to discuss its interest as a therapeutic target and to provide a review of the literature regarding ALK inhibitors. Mechanisms of acquired resistance are also reviewed.
Several ALK inhibitors have recently been developed, offering new treatment options in tumors driven by abnormal ALK signaling. However, as observed with other tyrosine kinase inhibitors, resistance has emerged in patients treated with these agents. The complexity of mechanisms of acquired resistance recently described suggests that other therapeutic options, including combination of ALK and other kinases targeted drugs, will be required in the future.
间变性淋巴瘤激酶（ALK）是一种酪氨酸激酶受体，最初是通过其参与与间变大细胞淋巴瘤相关的染色体易位而被发现的。然而，最近有证据表明，异常的 ALK 活性也参与了越来越多的肿瘤类型，如其他淋巴瘤、炎性肌纤维母细胞瘤、神经母细胞瘤和一些癌，包括非小细胞肺癌，这推动了 ALK 靶向治疗的研究进展。
本综述的第一个目的是描述目前对 ALK 酪氨酸激酶及其作为融合蛋白或通过突变在人类癌症发生中的作用的理解。第二个目标是讨论将其作为治疗靶点的意义，并对 ALK 抑制剂的文献进行综述。还回顾了获得性耐药的机制。
最近已经开发了几种 ALK 抑制剂，为异常 ALK 信号驱动的肿瘤提供了新的治疗选择。然而，正如在其他酪氨酸激酶抑制剂中观察到的那样，在接受这些药物治疗的患者中出现了耐药性。最近描述的获得性耐药机制的复杂性表明，未来需要其他治疗选择，包括 ALK 和其他激酶靶向药物的联合治疗。
