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

Hansson K, Radke K, Aaltonen K, Saarela J, Mañas A, Sjölund J, Smith EM, Pietras K, Påhlman S, Wennerberg K, Gisselsson D, Bexell D

Sci Transl Med 12 (562) - [2020-09-23; online 2020-09-25]

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.

Clinical Genomics Lund [Service]

PubMed 32967973

DOI 10.1126/scitranslmed.aba4434

Crossref 10.1126/scitranslmed.aba4434

pii: 12/562/eaba4434

Publications 9.5.0