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Expert Opin Investig Drugs. 2012 Jul;21(7):985-94. doi: 10.1517/13543784.2012.690031. Epub 2012 May 22.

Inhibitors of the anaplastic lymphoma kinase.

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  • 1University of Milano-Bicocca, Monza, Italy.



Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase normally expressed in the developing nervous tissue. Genetic alterations of ALK are associated with a number of cancers, including anaplastic large cell lymphoma (ALCL) and a subset of non-small cell lung cancer (NSCLC). Standard therapies for these diseases include surgery plus unspecific cytotoxic agents, with a low therapeutic window and significant treatment-associated systemic toxicity. A few small-molecule inhibitors of ALK kinase activity have been described in the recent years, some of which are currently undergoing clinical evaluation.


Literature was searched for all ALK inhibitors that have entered clinical investigation, including published research articles and meeting abstracts. Data on pharmacokinetics, safety and efficacy of crizotinib, as well as preliminary clinical data for second-generation compounds, are reviewed. The issue of drug resistance is discussed.


Understanding the specific genetic aberration that causes cancer development and progression allows major advances in cancer therapy. Along the same way shown by imatinib in chronic myeloid leukemia, compounds that selectively target ALK are bringing a revolution in the treatment of ALK-positive tumors. Crizotinib has just been approved, and new more potent ALK inhibitors will shortly follow. These molecules represent another excellent proof-of-principle for targeted therapy.

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