A Potential Role for the Inhibition of PI3K Signaling in Glioblastoma Therapy

作者：Stroebele Stephanie; Schneider Matthias; Schneele Lukas; Siegelin Markus D; Nonnenmacher Lisa; Zhou Shaoxia; Karpel Massle Georg; Westhoff Mike Andrew^*; Halatsch Marc Eric; Debatin Klaus Michael

来源：PLos One, 2015, 10(6): e0131670.

DOI：10.1371/journal.pone.0131670

Glioblastoma multiforme (GBM) is the most common primary brain tumor and among the most difficult to treat malignancies per se. In almost 90% of all GBM alterations in the PI3K/Akt/ mTOR have been found, making this survival cascade a promising therapeutic target, particular for combination therapy that combines an apoptosis sensitizer, such as a pharmacological inhibitor of PI3K, with an apoptosis inducer, such as radio- or chemotherapy. However, while in vitro data focusing mainly on established cell lines has appeared rather promising, this has not translated well to a clinical setting. In this study, we analyze the effects of the dual kinase inhibitor PI-103, which blocks PI3K and mTOR activity, on three matched pairs of GBM stem cells/differentiated cells. While blocking PI3K-mediated signaling has a profound effect on cellular proliferation, in contrast to data presented on two GBM cell lines (A172 and U87) PI-103 actually counteracts the effect of chemotherapy. While we found no indications for a potential role of the PI3K signaling cascade in differentiation, we saw a clear and strong contribution to cellular motility and, by extension, invasion. While blocking PI3K-mediated signaling concurrently with application of chemotherapy does not appear to be a valid treatment option, pharmacological inhibitors, such as PI-103, nevertheless have an important place in future therapeutic approaches.

• 出版日期2015-6-29