Drug sensitivity and resistance testing identifies PLK1 inhibitors and gemcitabine as potent drugs for malignant peripheral nerve sheath tumors.
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.
['Kolberg|Matthias|M|0000-0001-8288-5364', 'Bruun|Jarle|J|', 'Murumägi|Astrid|A|', 'Mpindi|John P|JP|', 'Bergsland|Christian H|CH|', 'Høland|Maren|M|', 'Eilertsen|Ina A|IA|', 'Danielsen|Stine A|SA|', 'Kallioniemi|Olli|O|', 'Lothe|Ragnhild A|RA|']
D017209:Apoptosis D018797:Cell Cycle Proteins D045744:Cell Line, Tumor D002986:Clinical Trials as Topic D003841:Deoxycytidine D019008:Drug Resistance, Neoplasm D015972:Gene Expression Regulation, Neoplastic D006801:Humans D018317:Nerve Sheath Neoplasms D047428:Protein Kinase Inhibitors D017346:Protein Serine-Threonine Kinases D011518:Proto-Oncogene Proteins D015203:Reproducibility of Results D012262:Ribonucleoside Diphosphate Reductase D025521:Tumor Suppressor Proteins
MPNST Schwann cell drug screen pharmacology