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Tucker et al. Cancer Drug Resist 2019;2:803-12 I http://dx.doi.org/10.20517/cdr.2019.09 Page 807

ALK

ALK

MYCN

MYCN MYCN

Transcriptional
CDK
inhibitors

Figure 1. A summary of the signaling connections between ALK and MYCN in neuroblastoma. The red boxes describe current therapeutic
approaches that are being pursued either preclinically or in clinical studies

Ceritinib, which received USA Food and Drug Administration approval in 2014 for treatment of patients
with ALK-rearranged metastatic non-small cell lung cancer (NSCLC), has shown efficacy above that of
[37]
Crizotinib in neuroblastoma models . However, its success in neuroblastoma patients is yet not fully
[38]
evaluated, apart from a favorable case report for a tumor harboring an ALK I1171T mutation . I1171T is
a gain-of function ALK mutation, located in the neuroblastoma mutation hotspot of ALK, at the αC-helix
in the amino-terminal lobe of the kinase. The most common neuroblastoma-associated mutations at this
hotspot are F1174, R1275 and F1274, each with different degrees of transforming ability and differential
sensitivities to available inhibitors [2,39] . A screen of known neuroblastoma-associated ALK mutations
utilizing recombinant ALK variants, revealed that response to crizotinib correlated with a relatively
reduced affinity of the mutant kinase for ATP. For example, ALK F1174L results in higher ATP-binding
[2]
affinity, predicting resistance to crizotinib . Much attention has been upon the potential of the third-
generation ALK inhibitor, Lorlatinib, for which exceptional preclinical evidence of its efficacy against the
Crizotinib-resistant ALK F1174L has been published [40,41] . Lorlatinib was initially developed for NSCLC
patients requiring targeted therapy against ALK for brain tumor metastases, as it has good Central
[42]
nervous system (CNS) availability . This could become a necessity for children with neuroblastoma,
as relapses within the CNS may become more frequent following the introduction of immunotherapy
into standard therapy. Based on this evidence, Lorlatinib is now available in an international study for
children with relapsed ALK mutant neuroblastoma. Other ALK inhibitors demonstrating good preclinical
rationale for neuroblastoma include Alectinib and Entrectinib [43,44] . Alectinib shows activity against RET,
a downstream target of ALK in neuroblastoma, which may increase its effectiveness in this form of the
disease . Entrectinib inhibits both ALK and the TRK receptors; TRKb is associated with poor prognosis
[45]
in neuroblastoma. Both these compounds are therefore a priority for further pediatric studies.

Although the standard route for the evaluation of novel compounds is through early phase clinical studies
in relapsing or treatment-refractory disease, there is strong preclinical rationale for the combination of