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Targeting ALK in neuroblastoma—preclinical and clinical advancements

Nature Reviews Clinical Oncology volume 9, pages 391–399 (2012)Cite this article

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Abstract

Despite improvements in cancer therapies in the past 50 years, neuroblastoma remains a devastating clinical problem and a leading cause of childhood cancer deaths. Advances in treatments for children with high-risk neuroblastoma have, until recently, involved addition of cytotoxic therapy to dose-intensive regimens. In this era of targeted therapies, substantial efforts have been made to identify optimal targets for different types of cancer. The discovery of hereditary and somatic activating mutations in the oncogene ALK has now placed neuroblastoma among other cancers, such as melanoma and non-small-cell lung cancer (NSCLC), which benefit from therapies with oncogene-specific small-molecule tyrosine kinase inhibitors. Crizotinib, a small-molecule inhibitor of ALK, has transformed the landscape for the treatment of NSCLC harbouring ALK translocations and has demonstrated activity in preclinical models of ALK-driven neuroblastomas. However, inhibition of mutated ALK is complex when compared with translocated ALK and remains a therapeutic challenge. This Review discusses the biology of ALK in the development of neuroblastoma, preclinical and clinical progress with the use of ALK inhibitors and immunotherapy, challenges associated with resistance to such therapies and the steps being taken to overcome some of these hurdles.

Key Points

  • The discovery of germline and somatic mutations in ALK provides the first tractable oncogenic target in neuroblastoma, prompting the initiation of a phase I–II trial of the ALK inhibitor crizotinib

  • ALK is mutated in 8% of all neuroblastoma cases; mutations are distributed across the range of phenotypes and predict for an inferior outcome

  • Full-length ALK is expressed on the surface of neuroblastoma tumours in both the presence and absence of a genetic alteration, suggesting that ALK antibody therapy is relevant in neuroblastoma

  • The F1174L mutation in ALK results in de novo resistance in neuroblastoma and has emerged as a resistance mechanism in ALK-translocated tumours treated with crizotinib

  • Structural and biochemical data suggest that the increase in ATP-binding affinity for the F1174L-mutated ALK can be overcome with higher doses of crizotinib

  • Stratification of patients based on ALK alteration status will likely become an integral part of frontline therapy for patients with high-risk neuroblastoma

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Figure 1: Schematic representation of ALK protein structure and mutations found in neuroblastoma.
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Acknowledgements

This work is supported in part by grants from the National Institute of Health (R01-CA140198), the Children's Oncology Group, the Carly Hillman Fund and the US Army Peer-Reviewed Medical Research Program (W81XWH-10-1-0212/3) granted to Y. P. Mossé.

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  1. Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, 3501 Civic Center Boulevard, Philadelphia, 19104, PA, USA

    Erica L. Carpenter & Yael P. Mossé

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Y. P. Mossé declares that she has received research funding from Pfizer. E. L. Carpenter declares no competing interests.

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Carpenter, E., Mossé, Y. Targeting ALK in neuroblastoma—preclinical and clinical advancements. Nat Rev Clin Oncol 9, 391–399 (2012). https://doi.org/10.1038/nrclinonc.2012.72

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