HGG-25. Targeting KLF5 reduces tumorigenic phenotype in a murine glioblastoma (GBM) model

Abstract

Sex differences are evident in the incidence, therapeutic response and survival of patients with various cancers including the most common, aggressive and incurable GBM. We generated a murine GBM model of male and female astrocytes with dual loss of NF1 and P53 that yielded a sex-biased transformation of the astrocytes with male cells being significantly more tumorigenic and therapeutically resistant compared to female cells. In our current work, we aimed to delineate the molecular mechanisms driving this sex-biased tumorigenic phenotype in order to deliver therapies that are more effective to patients with GBM. We examined the inhibition of KLF5 on tumorigenic phenotypes using cellular bio-functional assays. We used barcoded transposon calling cards to determine the genomic localization of KLF5 and the differentially induced gene expression in male versus female GBM cells. Chemical inhibition or shRNA knock-down of KLF5 significantly reduced proliferation, migration, clonogenic stem-cell frequency and survival, but increase apoptosis in male and female GBM cells. Interestingly, male, but not female, GBM cells exhibited an increased migratory phenotype after radiation that inhibition of KLF5 significantly reduced. Moreover, KLF5 inhibition significantly reduced the protein expression of tumorigenic PDGFRB, AKT, ERK and the stem marker Sox-2. Transposon calling cards mapped unique KLF5 genomic localization in male versus female GBM cells with significantly differential gene expression profiles between the two. The top genes induced by KLF5 in male cells were primarily affiliated with poorer prognosis and reduced survival, whereas in female cells they were affiliated with better prognosis and improved survival in patients with cancer. Our findings provide a promising exploratory avenue for KLF5 as a therapeutic target in GBM and warrants further investigation in order to delineate the precise molecular mechanisms driving this antitumor response so that targeted therapy would be more effective taking into consideration the sex-differences in patients with GBM.