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

Guan, Jikui ; Fransson, Susanne ; Siaw, Joachim Tetteh LU orcid ; Treis, Diana ; Van Den Eynden, Jimmy ; Chand, Damini ; Umapathy, Ganesh ; Ruuth, Kristina ; Svenberg, Petter and Wessman, Sandra , et al. (2018) In Cold Spring Harbor Molecular Case Studies 4(4).
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... (More)

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 ALKI1171T 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 LCMS/ MS phosphoproteomics analysis indicated a decrease in ALK signaling in response to ceritinib. Ceritinib was therefore selected for treatment in this child. Monotherapy with ceritinibwas 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.

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publishing date
type
Contribution to journal
publication status
published
subject
in
Cold Spring Harbor Molecular Case Studies
volume
4
issue
4
article number
a002550
publisher
Cold Spring Harbor Laboratory Press (CSHL)
external identifiers
  • pmid:29907598
  • scopus:85060772264
DOI
10.1101/mcs.a002550
language
English
LU publication?
no
additional info
Publisher Copyright: © 2018 Guan et al.
id
a8b8d69c-011c-41d2-96f4-8f28824b9790
date added to LUP
2025-03-19 11:48:35
date last changed
2025-06-11 17:57:08
@article{a8b8d69c-011c-41d2-96f4-8f28824b9790,
  abstract     = {{<p>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 ALKI1171T 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 LCMS/ MS phosphoproteomics analysis indicated a decrease in ALK signaling in response to ceritinib. Ceritinib was therefore selected for treatment in this child. Monotherapy with ceritinibwas 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.</p>}},
  author       = {{Guan, Jikui and Fransson, Susanne and Siaw, Joachim Tetteh and Treis, Diana and Van Den Eynden, Jimmy and Chand, Damini and Umapathy, Ganesh and Ruuth, Kristina and Svenberg, Petter and Wessman, Sandra and Shamikh, Alia and Jacobsson, Hans and Gordon, Lena and Stenman, Jakob and Svensson, Pär Johan and Hansson, Magnus and Larsson, Erik and Martinsson, Tommy and Palmer, Ruth H. and Kogner, Per and Hallberg, Bengt}},
  language     = {{eng}},
  number       = {{4}},
  publisher    = {{Cold Spring Harbor Laboratory Press (CSHL)}},
  series       = {{Cold Spring Harbor Molecular Case Studies}},
  title        = {{Clinical response of the novel activating ALK-I1171T mutation in neuroblastoma to the ALK inhibitor ceritinib}},
  url          = {{http://dx.doi.org/10.1101/mcs.a002550}},
  doi          = {{10.1101/mcs.a002550}},
  volume       = {{4}},
  year         = {{2018}},
}