title: 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.affiliation: Cell Biology Program and James Birrell Laboratories, The Hospital for Sick Children, Ontario, Canada.
authors.forename: Natalie
authors.initials: N
authors.lastname: Grinshtein
authors.forename: Alessandro
authors.initials: A
authors.lastname: Datti
authors.forename: Mayumi
authors.initials: M
authors.lastname: Fujitani
authors.forename: David
authors.initials: D
authors.lastname: Uehling
authors.forename: Michael
authors.initials: M
authors.lastname: Prakesch
authors.forename: Methvin
authors.initials: M
authors.lastname: Isaac
authors.forename: Meredith S
authors.initials: MS
authors.lastname: Irwin
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Wrana
authors.forename: Rima
authors.initials: R
authors.lastname: Al-Awar
authors.forename: David R
authors.initials: DR
authors.lastname: Kaplan
mesh_terms: D000465:Algorithms; D000818:Animals; D001932:Brain Neoplasms / Q000473:pathology / Q000517:prevention & control*; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors*; D002478:Cells, Cultured; D057166:High-Throughput Screening Assays; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D058990:Molecular Targeted Therapy / Q000379:methods; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000473:pathology; D009447:Neuroblastoma / Q000473:pathology / Q000517:prevention & control*; D047428:Protein Kinase Inhibitors / Q000032:analysis / Q000302:isolation & purification* / Q000627:therapeutic use*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D011621:Pteridines / Q000494:pharmacology / Q000627:therapeutic use; D054852:Small Molecule Libraries / Q000032:analysis*; D023041:Xenograft Model Antitumor Assays; D000097869:Polo-Like Kinase 1
chemical_list: D018797:Cell Cycle Proteins; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D011621:Pteridines; D054852:Small Molecule Libraries; D000097869:Polo-Like Kinase 1; C518477:BI 2536