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Tucker et al. Cancer Drug Resist 2019;2:803-12 Cancer
DOI: 10.20517/cdr.2019.09 Drug Resistance

Review Open Access

Targeting MYCN and ALK in resistant and relapsing
neuroblastoma

Elizabeth R Tucker, Evon Poon, Louis Chesler

Division of Clinical Studies, The Institute of Cancer Research, Sutton, SM2 5NG, UK.
Correspondence to: Prof. Louis Chesler, Paediatric Solid Tumour Biology and Therapeutics Team, The Institute of Cancer
Research, Cotswold Road, Sutton, Surrey, SM2 5NG, UK. E-mail: louis.chesler@icr.ac.uk

How to cite this article: Tucker ER, Poon E, Chesler L. Targeting MYCN and ALK in resistant and relapsing neuroblastoma. Cancer
Drug Resist 2019;2:803-12. http://dx.doi.org/10.20517/cdr.2019.09

Received: 20 Feb 2019 First Decision: 17 Apr 2019 Revised: 11 May 2019 Accepted: 21 May 2019 Published: 19 Sep 2019
Science Editor: Helen M. Coley Copy Editor: Han-juan Zhang Production Editor: Jing Yu

Abstract

Neuroblastoma, a tumor of peripheral nerve, is the most common solid tumor of young children. In high-risk disease,
which comprises approximately half of patients, death from chemotherapy-resistant, metastatic relapse is very
frequent. Children who relapse exhibit clonal enrichment of two genomic alterations: high-level amplification of the
MYCN oncogene, and kinase domain mutations of the anaplastic lymphoma kinase (ALK) gene. Overall survival in
this patient cohort is less than 15% at 3 years, and there are few options for rationally targeted therapy. Neuroblastoma
patients exhibit de novo resistance to many existing ALK inhibitors, and no clinical therapeutics to target MYCN
have yet been developed. This review outlines the international efforts to uncover mechanisms of oncogenic action
that are therapeutically targetable using small-molecule inhibitors. We describe a mechanistic interaction in which
ALK upregulates MYCN transcription, and discuss clinical trials emerging to develop transcriptional inhibitors of
MYCN, and to identify effective inhibitors of ALK in neuroblastoma patients.

Keywords: Neuroblastoma, anaplastic lymphoma kinase, MYCN, therapeutics

INTRODUCTION
Neuroblastoma is a malignancy of the developing sympathetic nervous system with up to 100 UK children
newly diagnosed each year. The risk stratification of neuroblastoma is highly complex and under constant
review in order to identify children who may require more aggressive treatment up-front in an effort to
prevent relapse, which is almost uniformly fatal. Most recently, a subgroup of ultra-high-risk patients was

© The Author(s) 2019. Open Access This article is licensed under a Creative Commons Attribution 4.0
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