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Cold Spring Harb Mol Case Stud. 2018 Aug 1;4(4). pii: a002550. doi: 10.1101/mcs.a002550. Print 2018 Aug.

Clinical response of the novel activating ALK-I1171T mutation in neuroblastoma to the ALK inhibitor ceritinib.

Author information

1
Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg 40530, Sweden.
2
Children's Hospital Affiliated to Zhengzhou University, 450018 Zhengzhou, China.
3
Department of Pathology and Genetics, Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg 40530, Sweden.
4
Childhood Cancer Research Unit, Department of Women's and Children's Health, and Pediatric Oncology Program Karolinska University Hospital, Stockholm 17176, Sweden.
5
Institute of Molecular Biology, Umeå University, Umeå 90187, Sweden.
6
Department of Oncology-Pathology, Karolinska Institutet, Stockholm 17176, Sweden.
7
Department of Clinical Pathology, Karolinska University Hospital, Stockholm 17176, Sweden.
8
Department of Radiology, Karolinska University Hospital, Stockholm 17176, Sweden.
9
Department of Pediatric Radiology, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm 17176, Sweden.
10
Department of Pediatric Surgery, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm 17176, Sweden.
11
Department of Pediatrics and Pathology, Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg 40530, Sweden.

Abstract

Tumors with anaplastic lymphoma kinase (ALK) fusion rearrangements, including non-small-cell lung cancer and anaplastic large cell lymphoma, are highly sensitive to ALK tyrosine kinase inhibitors (TKIs), underscoring the notion that such cancers are addicted to ALK activity. Although mutations in ALK are heavily implicated in childhood neuroblastoma, response to the ALK TKI crizotinib has been disappointing. Embryonal tumors in patients with DNA repair defects such as Fanconi anemia (FA) often have a poor prognosis, because of lack of therapeutic options. Here we report a child with underlying FA and ALK mutant high-risk neuroblastoma responding strongly to precision therapy with the ALK TKI ceritinib. Conventional chemotherapy treatment caused severe, life-threatening toxicity. Genomic analysis of the initial biopsy identified germline FANCA mutations as well as a novel ALK-I1171T variant. ALK-I1171T generates a potent gain-of-function mutant, as measured in PC12 cell neurite outgrowth and NIH3T3 transformation. Pharmacological inhibition profiling of ALK-I1171T in response to various ALK TKIs identified an 11-fold improved inhibition of ALK-I1171T with ceritinib when compared with crizotinib. Immunoaffinity-coupled LC-MS/MS phosphoproteomics analysis indicated a decrease in ALK signaling in response to ceritinib. Ceritinib was therefore selected for treatment in this child. Monotherapy with ceritinib was well tolerated and resulted in normalized catecholamine markers and tumor shrinkage. After 7.5 mo treatment, the residual primary tumor shrunk, was surgically removed, and exhibited hallmarks of differentiation together with reduced Ki67 levels. Clinical follow-up after 21 mo treatment revealed complete clinical remission including all metastatic sites. Therefore, ceritinib presents a viable therapeutic option for ALK-positive neuroblastoma.

KEYWORDS:

abnormality of the enteric ganglia; anaplastic large-cell lymphoma; neuroblastoma

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