New developments in the treatment of ALK-driven malignancies

Author(s): Luca Mologni & Carlo Gambacorti-Passerini

ALK has been recognized as a therapeutic target in several neoplasias, including anaplastic large cell lymphoma, non-small-cell lung cancer, neuroblastoma and colorectal cancer. Both chromosomal rearrangements, leading to the expression of fusion kinases, and kinase-activating point mutations, have been found to trigger the oncogenic activation of ALK. ALK-positive cancers are highly dependent on ALK catalytic activity. Since the normal, wild-type ALK gene is expressed at low levels in a limited population of nervous tissue cells, the targeting of oncogenic ALK proteins has great therapeutic value. Hence, a large effort is ongoing worldwide to develop small-molecule inhibitors of ALK. One compound has been approved for the treatment of ALK-positive non-small-cell lung cancer and a number of second-generation compounds are undergoing clinical evaluation. Here, we review the molecular biology of normal and oncogenic ALK, its involvement in the pathogenesis of cancer and the current status of ALK inhibitors research, including preclinical and clinical development and acquired resistance to ALK inhibition. The results obtained so far in ALK-positive tumors emphasize the importance of a deep understanding of the genetic alterations that cause transformation, in order to achieve major advances in cancer therapy.