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

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

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.

MeSH terms

  • Apoptosis / drug effects
  • Cell Cycle Proteins / antagonists & inhibitors*
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • Cell Line, Tumor
  • Clinical Trials as Topic
  • Deoxycytidine / analogs & derivatives*
  • Deoxycytidine / pharmacology
  • Deoxycytidine / therapeutic use
  • Drug Resistance, Neoplasm* / drug effects
  • Drug Resistance, Neoplasm* / genetics
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Nerve Sheath Neoplasms / drug therapy*
  • Nerve Sheath Neoplasms / enzymology*
  • Nerve Sheath Neoplasms / genetics
  • Nerve Sheath Neoplasms / pathology
  • 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
  • Proto-Oncogene Proteins / antagonists & inhibitors*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Reproducibility of Results
  • Ribonucleoside Diphosphate Reductase / genetics
  • Ribonucleoside Diphosphate Reductase / metabolism
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism

Substances

  • Cell Cycle Proteins
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins
  • Tumor Suppressor Proteins
  • Deoxycytidine
  • gemcitabine
  • ribonucleotide reductase M2
  • RRM1 protein, human
  • Ribonucleoside Diphosphate Reductase
  • Protein-Serine-Threonine Kinases
  • polo-like kinase 1