DDDR-07 - Evaluating the role of the PIK3CB pathway in temozolomide resistance in glioblastoma using the Genomics of Drug Sensitivity in Cancer (GDSC) and Cancer Cell Line Encyclopedia (CCLE) databases

Glioblastoma multiforme (GBM) is a lethal primary brain cancer with a median survival of 14.6 months despite standard treatment of maximal surgical resection, radiotherapy, and temozolomide (TMZ). Recent research has identified PIK3CB/p110β as the most important regulator of AKT activation and GBM cell survival. Utilizing the pharmacogenomic databases Genomics of Drug Sensitivity in Cancer (GDSC) and Cancer Cell Line Encyclopedia (CCLE), we sought to elucidate the relationship between PIK3CB mRNA expression or AKT phosphorylation and GBM treatment resistance. We first identified cell lines with matched PI3K isoform mRNA expression, protein expression (AKT phosphorylation at S473 and T308; reverse phase protein array) and drug sensitivity (defined by the area under the curve; AUC) from the GDSC1 and CCLE databases. Associations between PI3K isoforms, AKT phosphorylation, and drug sensitivities were reported by fitting univariable and multivariable linear regression models with and without interaction terms to communicate the effects of AKT phosphorylation conditional on PIK3CB levels. We found that AKT phosphorylation and PIK3CB mRNA data together performed better as a biomarker in predicting therapeutic response to p110β-selective inhibitors than each variable alone, specifically we found that AKT phosphorylation at T308 was negatively related to p110β-selective inhibitor AZD6482 sensitivity at low PIK3CB expression levels (B = -0.069, p = 0.0513) and this relationship disappeared at higher expression levels (B = 0.04, p = 0.176) with an interaction at near statistical significance (p = 0.0674). We found that PIK3CB mRNA levels were significantly positively associated with TMZ resistance in GBM (B=0.019, p=0.0211) while other PI3K isoforms were not. While AKT phosphorylation is currently used as a biomarker for PI3K pathway inhibitors, in this study, we demonstrate that both PIK3CB mRNA and AKT phosphorylation together was a significant biomarker in sensitivity to p110β inhibitors as compared to assessing each independently. Furthermore, PIK3CB was implicated in TMZ resistance in GBM as compared to other catalytic isoforms.