Small molecule kinase inhibitor screen identifies polo-like kinase 1 as a target for neuroblastoma tumor-initiating cells.

Abstract

Neuroblastoma (NB) is an often fatal pediatric tumor of neural crest origin. We previously isolated NB tumor-initiating cells (NB TIC) from bone marrow metastases that resemble cancer stem cells and form metastatic NB in immunodeficient animals with as few as ten cells. To identify signaling pathways important for the survival and self-renewal of NB TICs and potential therapeutic targets, we screened a small molecule library of 143 protein kinase inhibitors, including 33 in clinical trials. Cytostatic or cytotoxic drugs were identified that targeted PI3K (phosphoinositide 3-kinase)/Akt, PKC (protein kinase C), Aurora, ErbB2, Trk, and Polo-like kinase 1 (PLK1). Treatment with PLK1 siRNA or low nanomolar concentrations of BI 2536 or BI 6727, PLK1 inhibitors in clinical trials for adult malignancies, were cytotoxic to TICs whereas only micromolar concentrations of the inhibitors were cytotoxic for normal pediatric neural stem cells. Furthermore, BI 2536 significantly inhibited TIC tumor growth in a therapeutic xenograft model, both as a single agent and in combination with irinotecan, an active agent for relapsed NB. Our findings identify candidate kinases that regulate TIC growth and survival and suggest that PLK1 inhibitors are an attractive candidate therapy for metastatic NB.

• Authors: Natalie Grinshtein, Alessandro Datti, Mayumi Fujitani, David Uehling, Michael Prakesch, Methvin Isaac, Meredith S Irwin, Jeffrey L Wrana, Rima Al-Awar, David R Kaplan
• Journal: Cancer research (Cancer Res) Vol. 71 Issue 4 Pg. 1385-95 (Feb 15 2011) ISSN: 1538-7445 [Electronic] United States
• PMID: 21303981 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Validation Study)
• Copyright: ©2011 AACR.

Chemical References

• BI 2536
• Cell Cycle Proteins
• Protein Kinase Inhibitors
• Proto-Oncogene Proteins
• Pteridines
• Small Molecule Libraries
• Protein Serine-Threonine Kinases
• polo-like kinase 1

Topics

• Algorithms
• Animals
• Brain Neoplasms (pathology, prevention & control)
• Cell Cycle Proteins (antagonists & inhibitors)
• Cells, Cultured
• High-Throughput Screening Assays
• Humans
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Molecular Targeted Therapy (methods)
• Neoplastic Stem Cells (drug effects, pathology)
• Neuroblastoma (pathology, prevention & control)
• Protein Kinase Inhibitors (analysis, isolation & purification, therapeutic use)
• Protein Serine-Threonine Kinases (antagonists & inhibitors)
• Proto-Oncogene Proteins (antagonists & inhibitors)
• Pteridines (pharmacology, therapeutic use)
• Small Molecule Libraries (analysis)
• Xenograft Model Antitumor Assays