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

Artikel i vetenskaplig tidskrift
Författare Jikui Guan
Susanne Fransson
Joachim T. Siaw
Diana Treis
Jimmy Van den Eynden
Damini Chand
Ganesh Umapathy
Kristina Ruuth
Alia Shamikh
Hans Jacobsson
Lena Gordon
Par-Johan Svensson
Magnus Hansson
Tommy Martinsson
Per Kogner
Ruth H. Palmer
Bengt Hallberg
Publicerad i Cold Spring Harbor molecular case studies
ISSN 2373-2873
Publiceringsår 2018
Publicerad vid Institutionen för biomedicin, avdelningen för medicinsk genetik och klinisk genetik
Institutionen för biomedicin, avdelningen för patologi
Institutionen för biomedicin, avdelningen för medicinsk kemi och cellbiologi
Språk en
Länkar dx.doi.org/10.1101/mcs.a002550
www.ncbi.nlm.nih.gov/entrez/query.f...
Ämneskategorier Biokemi och molekylärbiologi, Cell- och molekylärbiologi, Cancer och onkologi, Pediatrik

Sammanfattning

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. While 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, due to 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 germ-line 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. Mono-therapy with ceritinib was well tolerated and resulted in normalized catecholamine markers and tumor shrinkage. After 7.5 months treatment, residual primary tumor was surgically removed and exhibited hallmarks of differentiation together with reduced Ki67 levels. Clinical follow-up after 21 months treatment revealed complete clinical remission including all metastatic sites. Therefore, ceritinib presents a viable therapeutic option for ALK-positive neuroblastoma.

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