Inhibition of Farnesyltransferase Potentiates NOTCH-Targeted Therapy against Glioblastoma Stem Cells

Abstract

Summary: Accumulating evidence suggests that cancer cells with stem cell-like phenotypes drive disease progression and therapeutic resistance in glioblastoma (GBM). NOTCH regulates self-renewal and resistance to chemoradiotherapy in GBM stem cells. However, NOTCH-targeted γ-secretase inhibitors (GSIs) exhibited limited efficacy in GBM patients. We found that farnesyltransferase inhibitors (FTIs) significantly improved sensitivity to GSIs. This combination showed significant antineoplastic and radiosensitizing activities in GBM stem cells, whereas non-stem GBM cells were resistant. These combinatorial effects were mediated, at least partially, through inhibition of AKT and cell-cycle progression. Using subcutaneous and orthotopic GBM models, we showed that the combination of FTIs and GSIs, but not either agent alone, significantly reduced tumor growth. With concurrent radiation, this combination induced a durable response in a subset of orthotopic tumors. These findings collectively suggest that the combination of FTIs and GSIs is a promising therapeutic strategy for GBM through selectively targeting the cancer stem cell subpopulation. : NOTCH-targeted agents may selectively compromise glioblastoma stem cells. In this article, Wang and colleagues demonstrate that farnesyltransferase inhibitors significantly augmented the sensitivity of glioblastoma stem cells to γ-secretase inhibitors and improved tumor growth control in xenograft models. This combination therapy also promoted radiosensitivity and resulted in a durable response in orthotopic glioblastoma models with concurrent radiation. Keywords: Notch, glioblastoma stem cells, γ-secretase inhibitors, farnesyltransferase inhibitors