Selectively targeting PI3K isoforms to treat glioblastoma

The phosphatidylinositide 3-kinase (PI3K) family consists of four catalytic isoforms (PIK3CA, B, D, and G that encode p110alpha, beta, delta, and gamma, respectively), which play deviating roles in the formation and progression of different types of cancer such as breast and colon cancers. However, whether these PI3K isoforms function differently or equivalently in glioblastoma has not yet been explored. Glioblastoma is the most common and aggressive malignant glioma and patients often succumb to tumor recurrence, a progressive disease state that significantly contributes to the poor prognosis of glioblastoma. PI3K signaling is hyperactivated and mutated in glioblastoma; however, targeting PI3K to treat this cancer has not yet been successful. Given that PI3K isoforms are functionally divergent, it is very likely that selectively targeting PI3K catalytic isoforms is a more effective and discriminating approach to treating GBM. This possibility is supported by the following lines of evidence. Firstly, among four PI3K catalytic isoforms, PIK3CB is highly expressed in glioblastoma and high levels of PIK3CB exhibit the strongest correlation with the incidence, risk (time to develop recurrence), and survival of glioblastoma recurrence based upon expression data of PI3K isoforms and patient data from The Cancer Genome Atlas. Secondly, PI3K is often hyperactivated in glioblastoma cells with high levels of p110beta, but not other p110s, and depletion of p110beta inactivates, whereas knockdown of other p110s has no effect on, PI3K activity as well as glioblastoma cell survival. Thirdly, the selective activation of p110beta may be due primarily to a gap junction protein connexin 43 because this cell surface protein activates p110beta in p110beta-high glioblastoma cells through a selective interaction between connexin 43 and p110beta. Lastly, glioblastoma cells display differential responses to p110 isoform-selective inhibitors. Only p110beta selective inhibitors effectively activate apoptosis in, suppress the viability of, and impede the xenograft growth of p110beta hyperactivated glioblastoma cells. More importantly, p110beta inhibitors are much less toxic to normal astrocytes than other p110 inhibitors. These findings have revealed molecular details underlying the divergent roles of PI3K catalytic isoforms in glioblastoma, which will foster a rational design of more effective PI3K-based therapies for this deadly disease. Citation Format: Kevin J. Pridham, Lamvy Le, Sujuan Guo, Robin T. Varghese, Yanping Liang, Cara M. Rodgers, Gary R. Simonds, Deborah F. Kelly, Zhi Sheng. Selectively targeting PI3K isoforms to treat glioblastoma [abstract]. In: Proceedings of the AACR Special Conference on Targeting PI3K/mTOR Signaling; 2018 Nov 30-Dec 8; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(10_Suppl):Abstract nr A18.