ABSTRACT
Resistance to chemotherapies such as temozolomide is a major hurdle to effectively treat therapy-resistant glioblastoma. This challenge arises from the activation of phosphatidylinositol 3-kinase (PI3K), which makes it an appealing therapeutic target. However, non-selectively blocking PI3K kinases PI3Kα/ß/δ/γ has yielded undesired clinical outcomes. It is, therefore, imperative to investigate individual kinases in glioblastoma's chemosensitivity. Here, we report that PI3K kinases were unequally expressed in glioblastoma, with levels of PI3Kß being the highest. Patients deficient of O6-methylguanine-DNA-methyltransferase (MGMT) and expressing elevated levels of PI3Kß, defined as MGMT-deficient/PI3Kß-high, were less responsive to temozolomide and experienced poor prognosis. Consistently, MGMT-deficient/PI3Kß-high glioblastoma cells were resistant to temozolomide. Perturbation of PI3Kß, but not other kinases, sensitized MGMT-deficient/PI3Kß-high glioblastoma cells or tumors to temozolomide. Moreover, PI3Kß-selective inhibitors and temozolomide synergistically mitigated the growth of glioblastoma stem cells. Our results have demonstrated an essential role of PI3Kß in chemoresistance, making PI3Kß-selective blockade an effective chemosensitizer for glioblastoma.
