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

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http://hdl.handle.net/10138/322042

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Hansson , K , Radke , K , Aaltonen , K , Saarela , J , Manas , A , Sjolund , J , Smith , E M , Pietras , K , Pahlman , S , Wennerberg , K , Gisselsson , D & Bexell , D 2020 , ' Therapeutic targeting of KSP in preclinical models of high-risk neuroblastoma ' , Science translational medicine , vol. 12 , no. 562 , 4434 . https://doi.org/10.1126/scitranslmed.aba4434

Title: Therapeutic targeting of KSP in preclinical models of high-risk neuroblastoma
Author: Hansson, Karin; Radke, Katarzyna; Aaltonen, Kristina; Saarela, Jani; Manas, Adriana; Sjolund, Jonas; Smith, Emma M.; Pietras, Kristian; Pahlman, Sven; Wennerberg, Krister; Gisselsson, David; Bexell, Daniel
Contributor: University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Krister Wennerberg / Principal Investigator
Date: 2020-09-23
Language: eng
Number of pages: 16
Belongs to series: Science translational medicine
ISSN: 1946-6234
URI: http://hdl.handle.net/10138/322042
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 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.
Subject: SPINDLE PROTEIN INHIBITOR
KINASE 1
ARRY-520
CELLS
ANTAGONISTS
XENOGRAFTS
CHECKPOINT
GENOMICS
PATHWAY
AURORA
1182 Biochemistry, cell and molecular biology
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