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Clinical response of the novel activating ALK-I1171T mutation in neuroblastoma o the ALK inhibitor ceritinib
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2018 (English)In: Cold Spring Harbor Molecular Case Studies, ISSN 2373-2873, Vol. 4, no 4, article id a002550Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Cold Spring Harbor Laboratory Press (CSHL), 2018. Vol. 4, no 4, article id a002550
National Category
Cancer and Oncology Cell and Molecular Biology
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URN: urn:nbn:se:umu:diva-154087DOI: 10.1101/mcs.a002550ISI: 000450957400001PubMedID: 29907598OAI: oai:DiVA.org:umu-154087DiVA, id: diva2:1270105
Funder
Swedish Cancer Society, TMCAN2015/794Swedish Cancer Society, BHCAN15/775Swedish Cancer Society, RHP CAN15/391Swedish Cancer Society, PK CAN16/3625Swedish Childhood Cancer Foundation, TM PR2016-0147Swedish Childhood Cancer Foundation, BH 2015-80Swedish Childhood Cancer Foundation, 2014-150Swedish Childhood Cancer Foundation, RHP 2015-96Swedish Childhood Cancer Foundation, PK PR2014-0084Swedish Childhood Cancer Foundation, JG 2016-0011Swedish Childhood Cancer Foundation, SF 15-0061Swedish Childhood Cancer Foundation, DT 12-009Swedish Childhood Cancer Foundation, 12-002Swedish Research Council, RHP 2015-04466Swedish Research Council, TM 521-2014-3031Swedish Research Council, PK 2014-3036Swedish Research Council, BH 521-2012-2831Swedish Foundation for Strategic Research , RB13-0204Göran Gustafsson Foundation for Research in Natural Sciences and Medicine, RHP2016Available from: 2018-12-12 Created: 2018-12-12 Last updated: 2018-12-12Bibliographically approved

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Ruuth, Kristina

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Guan, JikuiSiaw, Joachim TettehVan den Eynden, JimmyRuuth, KristinaKogner, Per
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Department of Molecular Biology (Faculty of Science and Technology)
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