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

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Kolberg , M , Bruun , J , Murumagi , A , Mpindi , J P , Bergsland , C H , Holand , M , Eilertsen , I A , Danielsen , S A , Kallioniemi , O & Lothe , R A 2017 , ' Drug sensitivity and resistance testing identifies PLK1 inhibitors and gemcitabine as potent drugs for malignant peripheral nerve sheath tumors ' , Molecular oncology , vol. 11 , no. 9 , pp. 1156-1171 . https://doi.org/10.1002/1878-0261.12086

Title: Drug sensitivity and resistance testing identifies PLK1 inhibitors and gemcitabine as potent drugs for malignant peripheral nerve sheath tumors
Author: Kolberg, Matthias; Bruun, Jarle; Murumagi, Astrid; Mpindi, John P.; Bergsland, Christian H.; Holand, Maren; Eilertsen, Ina A.; Danielsen, Stine A.; Kallioniemi, Olli; Lothe, Ragnhild A.
Other contributor: University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Institute for Molecular Medicine Finland



Date: 2017-09
Language: eng
Number of pages: 16
Belongs to series: Molecular oncology
ISSN: 1878-0261
DOI: https://doi.org/10.1002/1878-0261.12086
URI: http://hdl.handle.net/10138/248406
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.
Subject: drug screen
MPNST
pharmacology
Schwann cell
NEUROFIBROMATOSIS TYPE-1 PATIENTS
SCHWANNOMA CELL-LINE
SOFT-TISSUE SARCOMA
PHASE-II
CANCER-THERAPY
IN-VITRO
KINASE 1
GENE
GROWTH
RAS
3122 Cancers
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