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Therapeutic targeting of KSP in preclinical models of high-risk neuroblastoma

Hansson, Karin LU ; Radke, Katarzyna LU ; Aaltonen, Kristina LU ; Saarela, Jani ; Mañas, Adriana LU ; Sjölund, Jonas LU ; Smith, Emma M LU ; Pietras, Kristian LU orcid ; Påhlman, Sven LU and Wennerberg, Krister , et al. (2020) In Science Translational Medicine 12(562).
Abstract

Neuroblastoma is a childhood malignancy with often dismal prognosis; relapse is common despite intense treatment. Here, we used human tumor organoids representing multiple MYCN-amplified high-risk neuroblastomas to perform a high-throughput drug screen with approved or emerging oncology drugs. Tumor-selective effects were calculated using drug sensitivity scores. Several drugs with previously unreported anti-neuroblastoma effects were identified by stringent selection criteria. ARRY-520, an inhibitor of kinesin spindle protein (KSP), was among those causing reduced viability. High expression of the KSP-encoding gene KIF11 was associated with poor outcome in neuroblastoma. Genome-scale loss-of-function screens in hundreds of human cancer... (More)

Neuroblastoma is a childhood malignancy with often dismal prognosis; relapse is common despite intense treatment. Here, we used human tumor organoids representing multiple MYCN-amplified high-risk neuroblastomas to perform a high-throughput drug screen with approved or emerging oncology drugs. Tumor-selective effects were calculated using drug sensitivity scores. Several drugs with previously unreported anti-neuroblastoma effects were identified by stringent selection criteria. ARRY-520, an inhibitor of kinesin spindle protein (KSP), was among those causing reduced viability. High expression of the KSP-encoding gene KIF11 was associated with poor outcome in neuroblastoma. Genome-scale loss-of-function screens in hundreds of human cancer cell lines across 22 tumor types revealed that KIF11 is particularly important for neuroblastoma cell viability. KSP inhibition in neuroblastoma patient-derived xenograft (PDX) cells resulted in the formation of abnormal monoastral spindles, mitotic arrest, up-regulation of mitosis-associated genes, and apoptosis. In vivo, KSP inhibition caused regression of MYCN-amplified neuroblastoma PDX tumors. Furthermore, treatment of mice harboring orthotopic neuroblastoma PDX tumors resulted in increased survival. Our results suggested that KSP inhibition could be a promising treatment strategy in children with high-risk neuroblastoma.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Science Translational Medicine
volume
12
issue
562
article number
eaba4434
publisher
American Association for the Advancement of Science (AAAS)
external identifiers
  • scopus:85091550904
  • pmid:32967973
ISSN
1946-6242
DOI
10.1126/scitranslmed.aba4434
project
Deciphering and targeting treatment resistant metastatic neuroblastoma
language
English
LU publication?
yes
additional info
Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
id
00c93ace-f24a-41c1-b4fc-79758562264d
date added to LUP
2020-09-25 12:40:03
date last changed
2024-04-17 15:35:51
@article{00c93ace-f24a-41c1-b4fc-79758562264d,
  abstract     = {{<p>Neuroblastoma is a childhood malignancy with often dismal prognosis; relapse is common despite intense treatment. Here, we used human tumor organoids representing multiple MYCN-amplified high-risk neuroblastomas to perform a high-throughput drug screen with approved or emerging oncology drugs. Tumor-selective effects were calculated using drug sensitivity scores. Several drugs with previously unreported anti-neuroblastoma effects were identified by stringent selection criteria. ARRY-520, an inhibitor of kinesin spindle protein (KSP), was among those causing reduced viability. High expression of the KSP-encoding gene KIF11 was associated with poor outcome in neuroblastoma. Genome-scale loss-of-function screens in hundreds of human cancer cell lines across 22 tumor types revealed that KIF11 is particularly important for neuroblastoma cell viability. KSP inhibition in neuroblastoma patient-derived xenograft (PDX) cells resulted in the formation of abnormal monoastral spindles, mitotic arrest, up-regulation of mitosis-associated genes, and apoptosis. In vivo, KSP inhibition caused regression of MYCN-amplified neuroblastoma PDX tumors. Furthermore, treatment of mice harboring orthotopic neuroblastoma PDX tumors resulted in increased survival. Our results suggested that KSP inhibition could be a promising treatment strategy in children with high-risk neuroblastoma.</p>}},
  author       = {{Hansson, Karin and Radke, Katarzyna and Aaltonen, Kristina and Saarela, Jani and Mañas, Adriana and Sjölund, Jonas and Smith, Emma M and Pietras, Kristian and Påhlman, Sven and Wennerberg, Krister and Gisselsson, David and Bexell, Daniel}},
  issn         = {{1946-6242}},
  language     = {{eng}},
  number       = {{562}},
  publisher    = {{American Association for the Advancement of Science (AAAS)}},
  series       = {{Science Translational Medicine}},
  title        = {{Therapeutic targeting of KSP in preclinical models of high-risk neuroblastoma}},
  url          = {{http://dx.doi.org/10.1126/scitranslmed.aba4434}},
  doi          = {{10.1126/scitranslmed.aba4434}},
  volume       = {{12}},
  year         = {{2020}},
}