Therapeutic targeting of KSP in preclinical models of high-risk neuroblastoma
(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.
(Less)
- author
- organization
-
- LUCC: Lund University Cancer Centre
- Molecular Pediatric Oncology (research group)
- Division of Translational Cancer Research
- Experimental oncology (research group)
- Molecular Lymphopoiesis (research group)
- Division of Molecular Hematology (DMH)
- Pathways of cancer cell evolution (research group)
- Division of Clinical Genetics
- publishing date
- 2020
- 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}}, }