Abstract 336: PIK3CB/p110B is a survival factor in glioblastoma

Abstract

Abstract Glioblastoma multiforme (GBM) is lethal even after surgical removal of the tumor, radiation, and chemotherapy. Residual tumor cells form an intractable tumor in nearly all patients within two years. Recurrent GBM is incurable due to resistance to current therapies. Inhibitors of PI3K (phosphatidylinositol-4,5-biphosphate 3-kinase)-a signaling pathway that causally contributes to tumor formation/recurrence-have been used to treat recurrent GBMs and achieved modest clinical effect. This is perhaps attributed to non-selective inhibition of PI3K isoforms, which yields intolerable toxicity. Class IA PI3K isoforms include three catalytic subunits (PIK3CA, B, or D that encodes p110α, β, or δ) and three regulatory subunits (PIK3R1-3 that encodes p85 isoforms). Our recent work indicates that PIK3CB levels positively correlate with the chances/risk of GBM recurrence, while being inversely associated with patient prognosis. This suggests that PIK3CB/p110β is important for GBM cell survival. To test this hypothesis, we first measured the expression of PI3K isoforms in a panel of 9 GBM cell lines. We found that U87MG, SF295, and U251 expressed much higher levels of p110β, coinciding with the levels of phosphorylated AKT. We then knocked down PIK3CA, B, and D in human U87MG cells and found that only depletion of PIK3CB/p110β resulted in an inactivation of downstream AKT. Moreover, knockdown of PIK3CB/p110β, but not other isoforms, induced substantial growth inhibition in U87MG, SF295 and U251 cells. This is congruent with the result that inhibition of PIK3CB/p110β activated apoptosis in U87MG cells. We also report that treatment of p110βhigh GBM cells with isoform specific inhibitors selectively represses the viability of these cells. Finally, we report that ectopic expression of p110β, but not p110α or δ, partially rescued U87MG cells from growth inhibition induced by TGX-221, a p110β-selective inhibitor. Collectively, our results demonstrate that PIK3CB/p110β is an important selective survival factor in GBM, underscoring the divergent roles of PI3K isoforms in GBM disease progression/recurrence and future therapeutic intervention. Citation Format: Kevin J. Pridham, Sujuan Guo, Zhi Sheng. PIK3CB/p110B is a survival factor in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 336. doi:10.1158/1538-7445.AM2017-336