Editorial
Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Clin Oncol. Oct 10, 2015; 6(5): 104-108
Published online Oct 10, 2015. doi: 10.5306/wjco.v6.i5.104
Current and future treatment of anaplastic lymphoma kinase-rearranged cancer
Luca Mologni
Luca Mologni, Molecular Oncology Lab, Department Health Sciences, University of Milano-Bicocca, 20900 Monza, Italy
Author contributions: Mologni L conceived the content and wrote the manuscript.
Supported by The Italian Association for Cancer Research, AIRC 2013 IG-14249.
Conflict-of-interest statement: The author declares no conflict of interest.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Luca Mologni, PhD, Molecular Oncology Lab, Department Health Sciences, University of Milano-Bicocca, Via Cadore 48, 20900 Monza, Italy. luca.mologni@unimib.it
Telephone: +39-02-64488148 Fax: +39-02-64488363
Received: May 19, 2015
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
Abstract

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.

Keywords: Anaplastic lymphoma kinase tyrosine kinase receptor; Protein kinase inhibitors; Drug resistance; Crizotinib; Drug combinations

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.