Stem-21disruption of Facilitates Chromatin Transcription (fact) Synergizes With Epidermal Growth Factor Receptor (egfr) Inhibition and Preferentially Targets Glioblastoma Stem Cells
Year: 2015
Type: article
Abstract: NF-κB activation can drive the pathogenesis and therapeutic resistance of glioblastoma (GBM) with aberrant epidermal growth factor receptor (EGFR) signaling serving as a key mechanism of activation. Over half of GBM patients harbor genomic alterations in EGFR, substantiating it as an attractive therapeutic target despite the overall disappointing results of clinical trials thus far. Causes for failure are myriad with redundant and alternative compensatory pathways involved as well as the presence of a cellular heterogeneity that includes a more treatment-resistant population termed glioblastoma stem cells (GSCs). We sought to explore the efficacy of targeting the NF-κB-signaling node using a combination therapy of the EGFR/HER2 inhibitor lapatinib with a novel small molecule, CBL0137, which disrupts NF-κB-mediated signaling through the inhibition of facilitates chromatin transcription (FACT), a histone chaperone complex shown to be predominantly expressed in undifferentiated cancers. CBL0137 is a structural analog of quinicrine, a 9-aminoacridine derivative that was originally used as an anti-malarial drug and is well tolerated by patients. Lapatinib and CBL0137 inhibited all patient-derived GBM cells tested synergistically, including the GSC subpopulation. Remarkably, compared to matched non-stem tumor cells (NSTCs), GSCs were extremely sensitive to CBL0137 monotherapy, which prompted us to further evaluate the impact of FACT inhibition on GSC biology. Protein levels of FACT were higher in the GSC subpopulation versus NSTCs and chemical or genetic disruption of FACT compromised GSC viability, self-renewal, symmetric cell division and tumor initiation. We identified FACT occupancy at the promoters of key GSC transcription factors with decreased expression upon FACT inhibition. Our novel observation of the preferential targeting of GSCs by CBL0137 supports further development of clinical trials combining CBL0137 and EGFR inhibitors in GBM.
Source: Neuro-Oncology
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2585839057