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Targeting a Plk1-Controlled Polarity Checkpoint in Therapy-Resistant Glioblastoma-Propagating Cells
Robin G Lerner1, Stefan Grossauer1, Banafsheh Kadkhodaei1
1Department of Neurosurgery, Brain Tumor Research Center, University of California San Francisco, San Francisco, California.
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.
Insights
Targeted BRAF/MAPK inhibitors are less effective against glioblastoma stem cells. Combining BRAF and polo-like kinase 1 (PLK1) inhibition overcomes this resistance, offering a promising new strategy for treating this challenging brain tumor.
Area of Science:
- Neuro-oncology
- Cancer Cell Biology
- Molecular Therapeutics
Background:
- Glioblastoma (GBM) treatment is hindered by therapy-resistant, stem-like tumor-propagating cells.
- BRAF/MAPK inhibitors are novel agents for GBM, but their impact on these resistant cells is unknown.
Purpose of the Study:
- To investigate the sensitivity of CD133(+) glioblastoma stem-like cells to BRAF/MAPK inhibition.
- To explore the potential of combination therapy targeting BRAF and polo-like kinase 1 (PLK1) in GBM.
Main Methods:
- Characterization of CD133(+) and CD133(-) cells from primary GBM lines.
- Assessment of BRAF/MAPK inhibitor effects on cell proliferation and cell cycle.
- Evaluation of BRAF and PLK1 dual inhibition in an orthotopic GBM xenograft model.
Main Results:
- CD133(+) cells showed reduced sensitivity to BRAF/MAPK inhibition compared to CD133(-) cells.
- CD133(+) cells displayed altered cell cycle progression (extended G2-M) and asymmetric divisions.
- Elevated polo-like kinase 1 (PLK1) activity was observed in CD133(+) cells.
- Combined BRAF and PLK1 inhibition yielded significantly enhanced antiproliferative and proapoptotic effects versus monotherapy.
Conclusions:
- PLK1 activity may regulate a polarity checkpoint, compensating for BRAF/MAPK inhibition in CD133(+) cells.
- Concurrent PLK1 inhibition is necessary to improve antitumor activity against therapy-resistant GBM stem cells.
- Combination BRAF/PLK1 inhibition presents a potential therapeutic strategy for overcoming GBM treatment resistance.
