title: Targeting a Plk1-Controlled Polarity Checkpoint in Therapy-Resistant Glioblastoma-Propagating Cells.
abstract: The treatment of glioblastoma (GBM) remains challenging in part due to the presence of stem-like tumor-propagating cells that are resistant to standard therapies consisting of radiation and temozolomide. Among the novel and targeted agents under evaluation for the treatment of GBM are BRAF/MAPK inhibitors, but their effects on tumor-propagating cells are unclear. Here, we characterized the behaviors of CD133(+) tumor-propagating cells isolated from primary GBM cell lines. We show that CD133(+) cells exhibited decreased sensitivity to the antiproliferative effects of BRAF/MAPK inhibition compared to CD133(-) cells. Furthermore, CD133(+) cells exhibited an extended G2-M phase and increased polarized asymmetric cell divisions. At the molecular level, we observed that polo-like kinase (PLK) 1 activity was elevated in CD133(+) cells, prompting our investigation of BRAF/PLK1 combination treatment effects in an orthotopic GBM xenograft model. Combined inhibition of BRAF and PLK1 resulted in significantly greater antiproliferative and proapoptotic effects beyond those achieved by monotherapy (P < 0.05). We propose that PLK1 activity controls a polarity checkpoint and compensates for BRAF/MAPK inhibition in CD133(+) cells, suggesting the need for concurrent PLK1 inhibition to improve antitumor activity against a therapy-resistant cell compartment.
authors.affiliation: Department of Neurosurgery, Brain Tumor Research Center, University of California San Francisco, San Francisco, California.
authors.forename: Robin G
authors.initials: RG
authors.lastname: Lerner
authors.affiliation: Department of Neurosurgery, Brain Tumor Research Center, University of California San Francisco, San Francisco, California.
authors.forename: Stefan
authors.initials: S
authors.lastname: Grossauer
authors.affiliation: Department of Neurosurgery, Brain Tumor Research Center, University of California San Francisco, San Francisco, California.
authors.forename: Banafsheh
authors.initials: B
authors.lastname: Kadkhodaei
authors.affiliation: Department of Neurosurgery, Brain Tumor Research Center, University of California San Francisco, San Francisco, California.
authors.forename: Ian
authors.initials: I
authors.lastname: Meyers
authors.affiliation: Department of Neurosurgery, Brain Tumor Research Center, University of California San Francisco, San Francisco, California.
authors.forename: Maxim
authors.initials: M
authors.lastname: Sidorov
authors.affiliation: Department of Neurosurgery, Brain Tumor Research Center, University of California San Francisco, San Francisco, California.
authors.forename: Katharina
authors.initials: K
authors.lastname: Koeck
authors.affiliation: Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Rintaro
authors.initials: R
authors.lastname: Hashizume
authors.affiliation: Department of Neurosurgery, Brain Tumor Research Center, University of California San Francisco, San Francisco, California.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Ozawa
authors.affiliation: Department of Neurosurgery, Brain Tumor Research Center, University of California San Francisco, San Francisco, California. Department of Pathology, University of California San Francisco, San Francisco, California.
authors.forename: Joanna J
authors.initials: JJ
authors.lastname: Phillips
authors.affiliation: Department of Neurosurgery, Brain Tumor Research Center, University of California San Francisco, San Francisco, California.
authors.forename: Mitchel S
authors.initials: MS
authors.lastname: Berger
authors.affiliation: Department of Neurosurgery, Brain Tumor Research Center, University of California San Francisco, San Francisco, California. Department of Pediatrics, University of California San Francisco, San Francisco, California.
authors.forename: Theodore
authors.initials: T
authors.lastname: Nicolaides
authors.affiliation: Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: C David
authors.initials: CD
authors.lastname: James
authors.affiliation: Department of Neurosurgery, Brain Tumor Research Center, University of California San Francisco, San Francisco, California. Helen Diller Comprehensive Cancer Research Center, University of California San Francisco, San Francisco, California. Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California San Francisco, University of California San Francisco, San Francisco, California. Claudia.petritsch@ucsf.edu.
authors.forename: Claudia K
authors.initials: CK
authors.lastname: Petritsch
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000473:pathology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D016764:Cell Polarity / Q000187:drug effects; D002469:Cell Separation; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D005909:Glioblastoma / Q000473:pathology*; D006801:Humans; D051379:Mice; D014411:Neoplastic Stem Cells / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors; D020133:Reverse Transcriptase Polymerase Chain Reaction; D023041:Xenograft Model Antitumor Assays; D000097869:Polo-Like Kinase 1
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D048493:Proto-Oncogene Proteins B-raf; D000097869:Polo-Like Kinase 1; C482119:BRAF protein, human