Targeting a Plk1-controlled polarity checkpoint in therapy-resistant glioblastoma-propagating cells

Robin G. Lerner, Stefan Grossauer, Banafsheh Kadkhodaei, Ian Meyers, Maxim Sidorov, Katharina Koeck, Rintaro Hashizume, Tomoko Ozawa, Joanna J. Phillips, Mitchel S. Berger, Theodore Nicolaides, C. David James, Claudia K. Petritsch*

*Corresponding author for this work

Research output: Contribution to journalArticle

20 Scopus citations

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 bymonotherapy (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 languageEnglish (US)
Pages (from-to)5355-5366
Number of pages12
JournalCancer Research
Volume75
Issue number24
DOIs
StatePublished - Dec 15 2015

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Lerner, R. G., Grossauer, S., Kadkhodaei, B., Meyers, I., Sidorov, M., Koeck, K., Hashizume, R., Ozawa, T., Phillips, J. J., Berger, M. S., Nicolaides, T., James, C. D., & Petritsch, C. K. (2015). Targeting a Plk1-controlled polarity checkpoint in therapy-resistant glioblastoma-propagating cells. Cancer Research, 75(24), 5355-5366. https://doi.org/10.1158/0008-5472.CAN-14-3689