Response to the combination of farnesyltransferase inhibitors and gamma-secretase inhibitors in glioblastoma stem cells

Notch-targeted gamma-secretase inhibitors (GSIs) exhibited limited efficacy in glioblastoma patients. We identified that farnesyltransferase inhibitors (FTIs) increased sensitivity to GSIs in glioblastoma stem cells. To interrogate the mechanisms mediating the interaction between these two classes of compounds, we studied the impact on gene expression profiles by the combination of tipifarnib (FTI) and RO4929097 (GSI). We found that this combination treatment significantly suppressed genes implicated cell cycle progression. Real-time PCR validated the activities of tipifarnib to modulate expression of cell cycle regulators. We also showed that RO4929097 sensitized glioblastoma stem cells to compounds targeting some of these cell cycle regulators, such as AURKB and CDK4/6. These results suggest that regulation of cell cycle progression partially mediates the ability of FTIs to sensitize glioblastoma stem cells to GSIs. Short-term cultures of CD133+ cells were derived and enriched from three glioblastoma xenograft lines and treated with 100 nM tipifarnib plus 100 nM RO4929097 for expression profiling assays.