1. Targeting a Plk1-Controlled Polarity Checkpoint in Therapy-Resistant Glioblastoma-Propagating Cells
- Author
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Lerner, Robin G, Grossauer, Stefan, Kadkhodaei, Banafsheh, Meyers, Ian, Sidorov, Maxim, Koeck, Katharina, Hashizume, Rintaro, Ozawa, Tomoko, Phillips, Joanna J, Berger, Mitchel S, Nicolaides, Theodore, James, C David, and Petritsch, Claudia K
- Subjects
Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Stem Cell Research ,Brain Cancer ,Rare Diseases ,Brain Disorders ,Cancer ,5.1 Pharmaceuticals ,Animals ,Antineoplastic Agents ,Brain Neoplasms ,Cell Cycle Checkpoints ,Cell Cycle Proteins ,Cell Line ,Tumor ,Cell Polarity ,Cell Separation ,Flow Cytometry ,Fluorescent Antibody Technique ,Glioblastoma ,Humans ,Mice ,Neoplastic Stem Cells ,Protein Serine-Threonine Kinases ,Proto-Oncogene Proteins ,Proto-Oncogene Proteins B-raf ,Reverse Transcriptase Polymerase Chain Reaction ,Xenograft Model Antitumor Assays ,Polo-Like Kinase 1 ,Oncology & Carcinogenesis ,Biochemistry and cell biology ,Oncology and carcinogenesis - 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.
- Published
- 2015