Published online Oct 10, 2015. doi: 10.5306/wjco.v6.i5.104
Peer-review started: May 20, 2015
First decision: July 10, 2015
Revised: July 16, 2015
Accepted: August 20, 2015
Article in press: August 21, 2015
Published online: October 10, 2015
Processing time: 146 Days and 13.4 Hours
Aberrant forms of the anaplastic lymphoma kinase (ALK) are involved in the pathogenesis of several types of cancer, including anaplastic large cell lymphoma, non-small-cell lung cancer (NSCLC), inflammatory myofibroblastic tumors, colorectal cancer, neuroblastoma and others. In general, the ALK catalytic domain is rearranged and fused to a dimerization domain encoded by an unrelated gene. Less frequently, full-length ALK is activated by point mutations. The common theme is unregulated firing of ALK downstream signalling, leading to uncontrolled cell division and increased cell survival. ALK-driven tumors can be treated with Crizotinib, an orally available dual ALK/MET inhibitor, currently approved for advanced ALK-positive NSCLCs. Crizotinib-treated patients achieve high response rates, with an excellent toxicity profile. However, drug-resistant disease often develops, particularly in NSCLC patients. The processes leading to drug resistance include both ALK-dependent (point mutations or gene amplification), as well as ALK-independent mechanisms, which are here briefly discussed. Recently, Ceritinib has been approved for Crizotinib-refractory NSCLC, further extending patients’ survival, but resistance again emerged. Novel ALK kinase inhibitors are currently under clinical development, showing great promise for improved efficacy in drug-resistance disease. It is opinion of the author that drug-resistance is likely to arise under any treatment, due to intrinsic heterogeneity and adaptability of cancer. To prevent or delay this phenomenon, we need to treat less advanced disease, with drugs that are rapidly effective in order not to allow enough time for tumor evolution, and we want to have more and more drugs with non-overlapping resistance profiles, for subsequent lines of targeted therapy. Finally, the use of drug combinations may exponentially decrease the chances of resistance.
Core tip: In this Editorial article, I discuss the issue of anaplastic lymphoma kinase (ALK) driven cancer and its specific treatment with selective ALK tyrosine kinase inhibitors. The problem of acquired drug resistance is shortly reviewed and clinical data with novel investigational ALK inhibitors are presented. The possibility of specific combination therapies is briefly discussed.