Journal
SCIENCE TRANSLATIONAL MEDICINE
Volume 12, Issue 562, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.aba4434
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Funding
- Swedish Cancer Society
- Swedish Childhood Cancer Foundation
- Swedish Research Council
- Strategic Cancer Research Program BioCARE
- Medical Faculty of Lund University
- Crafoord Foundation
- Jeanssons stiftelser
- Mary Beves Stiftelse for Barncancerforskning
- Ollie och Elof Ericssons stiftelser
- Berth von Kantzows stiftelse
- Royal Physiographic Society in Lund
- Per-Eric and Ulla Schyberg foundation
- Ake Wiberg Foundation
- Magnus Bergvall Foundation
- Marta Winklers stiftelse
- Gyllenstiernska Krapperupsstiftelsen
- Region Skane and Skane University Hospital
- University of Helsinki (HiLife)
- Biocenter Finland
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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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