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

• Published in: Molecular oncology 2017-09, Vol.11 (9), p.1156-1171
• Main Authors: Kolberg, Matthias, Bruun, Jarle, Murumägi, Astrid, Mpindi, John P., Bergsland, Christian H., Høland, Maren, Eilertsen, Ina A., Danielsen, Stine A., Kallioniemi, Olli, Lothe, Ragnhild A.
• Format: Article
• Language: English
• Subjects: Antimitotic agents; Antineoplastic agents; Apoptosis; Apoptosis - drug effects; Bone marrow; Cancer therapies; Cell Cycle Proteins - antagonists & inhibitors; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell Line, Tumor; Chemotherapy; Clinical trials; Clinical Trials as Topic; Copy number; Cytotoxicity; Deoxycytidine - analogs & derivatives; Deoxycytidine - pharmacology; Deoxycytidine - therapeutic use; Deoxyribonucleic acid; DNA; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - genetics; drug screen; Drug therapy; Drugs; Gemcitabine; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Humans; Kinases; Medical prognosis; Medicin och hälsovetenskap; MPNST; Nerve Sheath Neoplasms - drug therapy; Nerve Sheath Neoplasms - enzymology; Nerve Sheath Neoplasms - genetics; Nerve Sheath Neoplasms - pathology; Neurofibromin 1; Patients; Peripheral nerves; Pharmacogenomics; pharmacology; Polo-Like Kinase 1; Prognosis; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Protein Serine-Threonine Kinases - antagonists & inhibitors; Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - metabolism; Proteins; Proto-Oncogene Proteins - antagonists & inhibitors; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Radiation therapy; Reproducibility of Results; Ribonucleoside Diphosphate Reductase - genetics; Ribonucleoside Diphosphate Reductase - metabolism; Ribonucleotide reductase; Schwann cell; Schwann cells; Studies; Tumor cell lines; Tumor suppressor genes; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; Tumors
• ISSN: 1574-7891; 1878-0261; 1878-0261
• DOI: 10.1002/1878-0261.12086

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. Systematic screen of 300 approved and emerging drugs in seven cancer cell lines and two healthy controls identifies PLK1 inhibitors and gemcitabine as selective and specific drugs for malignant peripheral nerve sheath tumors.