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Mol Oncol. 2017 Sep;11(9):1156-1171. doi: 10.1002/1878-0261.12086. Epub 2017 Jul 5.

Drug sensitivity and resistance testing identifies PLK1 inhibitors and gemcitabine as potent drugs for malignant peripheral nerve sheath tumors.

Author information

1
Department of Molecular Oncology, Institute for Cancer Research, the Norwegian Radium Hospital, Oslo University Hospital, Norway.
2
Centre for Cancer Biomedicine, University of Oslo, Norway.
3
Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Finland.
4
Science for Life Laboratory, Solna, Sweden.
5
Department of Oncology and Pathology, Karolinska Institutet, Solna, Sweden.

Abstract

Patients with malignant peripheral nerve sheath tumor (MPNST), a rare soft tissue cancer associated with loss of the tumor suppressor neurofibromin (NF1), have poor prognosis and typically respond poorly to adjuvant therapy. We evaluated the effect of 299 clinical and investigational compounds on seven MPNST cell lines, two primary cultures of human Schwann cells, and five normal bone marrow aspirates, to identify potent drugs for MPNST treatment with few side effects. Top hits included Polo-like kinase 1 (PLK1) inhibitors (volasertib and BI2536) and the fluoronucleoside gemcitabine, which were validated in orthogonal assays measuring viability, cytotoxicity, and apoptosis. DNA copy number, gene expression, and protein expression were determined for the cell lines to assess pharmacogenomic relationships. MPNST cells were more sensitive to BI2536 and gemcitabine compared to a reference set of 94 cancer cell lines. PLK1, RRM1, and RRM2 mRNA levels were increased in MPNST compared to benign neurofibroma tissue, and the protein level of PLK1 was increased in the MPNST cell lines compared to normal Schwann cells, indicating an increased dependence on these drug targets in malignant cells. Furthermore, we observed an association between increased mRNA expression of PLK1, RRM1, and RRM2 in patient samples and worse disease outcome, suggesting a selective benefit from inhibition of these genes in the most aggressive tumors.

KEYWORDS:

MPNST ; Schwann cell; drug screen; pharmacology

PMID:
28556483
PMCID:
PMC5579334
DOI:
10.1002/1878-0261.12086
[Indexed for MEDLINE]
Free PMC Article

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