Abstract
Neuroblastoma (NBL) is an embryonic malignancy of the sympathetic nervous system and mostly affects children under the age of five. NBL is highly heterogeneous and ranges from spontaneously regressing to highly aggressive disease. One of the risk factors for poor prognosis are aberrations in the receptor tyrosine kinase anaplastic lymphoma kinase (ALK), which is involved in the normal development and function of the nervous system. ALK mutations lead to constitutive activation of ALK and its downstream signalling pathways, thus driving tumorigenesis. A wide range of steric ALK inhibitors has been synthesized, and several of these inhibitors are already in clinical use. Major challenges are acquired drug resistance to steric inhibitors and pathway evasion strategies of cancer cells upon targeted therapy. This review will give a comprehensive overview on ALK inhibitors in clinical use in high-risk NBL and on the potential and limitations of novel inhibitors. Because combinatory treatment regimens are probably less likely to induce drug resistance, a special focus will be on the combination of ALK inhibitors with drugs that either target downstream signalling pathways or that affect the survival and proliferation of cancer cells in general.
Highlights
Precision medicine is an expanding field within cancer treatment
This review provides an update on anaplastic lymphoma kinase (ALK) inhibitors administered alone or in combination with other targeted therapies in the treatment of NBL
The inhibition of the RAS/MAPK pathway poses a risk of severe adverse effects that were demonstrated in another study: the MEK1/2 inhibitor trametinib in combination with the ALK inhibitor TAE-684 led to the upregulation of MAPK feedback inhibition
Summary
Precision medicine is an expanding field within cancer treatment. Malignancies are increasingly divided into subcategories depending on their genetic features. A variety of genetic alterations (such as ABL [1], IDH2 [2] and PD-L1 [3]) can already be targeted, usually as a supplement to standard treatment regimes. ALK mutations, the kinase is among the most promising targets for personalized therapy. This review provides an update on ALK inhibitors administered alone or in combination with other targeted therapies in the treatment of NBL. The article summarizes the contents of recent publications on ALK inhibitors (especially [4,5,6,7]) but further includes results from recent clinical studies and novel research articles. The review gives a summary of the results of research studies focusing on ALK inhibition in combination with other (pathway-) specific inhibitors.
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