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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.

Original publication




Journal article


Cancer research

Publication Date





5355 - 5366


Department of Neurosurgery, Brain Tumor Research Center, University of California San Francisco, San Francisco, California.


Cell Line, Tumor, Animals, Humans, Mice, Glioblastoma, Brain Neoplasms, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins B-raf, Cell Cycle Proteins, Proto-Oncogene Proteins, Antineoplastic Agents, Fluorescent Antibody Technique, Flow Cytometry, Cell Separation, Xenograft Model Antitumor Assays, Reverse Transcriptase Polymerase Chain Reaction, Cell Polarity, Neoplastic Stem Cells, Cell Cycle Checkpoints