Anaplastic lymphoma kinase (ALK): structure, oncogenic activation, and pharmacological inhibition

Anaplastic lymphoma kinase was first described in 1994 as the NPM-ALK fusion protein that is expressed in the majority of anaplastic large-cell lymphomas. ALK is a receptor protein-tyrosine kinase that was more fully characterized in 1997. Physiological ALK participates in embryonic nervous system development, but its expression decreases after birth. ALK is a member of the Insulin Receptor superfamily and is most closely related to leukocyte tyrosine kinase (Ltk), which is a receptor protein-tyrosine kinase. Twenty different ALK-fusion proteins have been described that result from various chromosomal rearrangements, and they have been implicated in the pathogenesis of several diseases including anaplastic large-cell lymphoma, diffuse large B-cell lymphoma, and inflammatory myofibroblastic tumors. The EML4-ALK fusion protein and four other ALK-fusion proteins play a fundamental role in the development in about 5% of non-small cell lung cancers. The formation of dimers by the amino-terminal portion of the ALK fusion proteins results in the activation of the ALK protein kinase domain that plays a key role in the tumorigenic process. Downstream signaling from ALK fusion proteins involves the Ras/Raf/MEK/ERK1/2 cell proliferation module and the JAK/STAT cell survival pathway. Furthermore, nearly two dozen ALK activating mutations participate in the pathogenesis of childhood neuroblastomas along with ALK overexpression. The occurrence of oncogenic ALK, particularly in non-small cell lung Cancer, has generated considerable interest and effort in developing ALK inhibitors. Currently, crizotinib has been approved by the US Food and Drug Administration for the treatment of ALK-positive non-small cell lung Cancer along with an approved fluorescence in situ hybridization kit used for the diagnosis of the disease. The emergence of crizotinib drug resistance with a median occurrence at approximately 10 months after the initiation of therapy has stimulated the development of second-generation drugs for the treatment of non-small cell lung Cancer and other disorders. About 28% of the cases of crizotinib resistance are related to nearly a dozen different mutations of ALK in the EML4-ALK fusion protein; the other cases of resistance are related to the upregulation of alternative signaling pathways or to undefined mechanisms. It is remarkable that the EML4-ALK fusion protein was discovered in 2007 and crizotinib was approved for the treatment of ALK-positive non-small cell lung Cancer in 2011, which is a remarkably short timeframe in the overall scheme of drug discovery.