Selective regulation of chemosensitivity in glioblastoma by phosphatidylinositol 3-kinase beta
Kevin J. Pridham,
Kasen R. Hutchings,
Patrick Beck,
Min Liu,
Eileen Xu,
Erin Saechin,
Vincent Bui,
Chinkal Patel,
Jamie Solis,
Leah Huang,
Allison Tegge,
Deborah F. Kelly,
Zhi Sheng
Affiliations
Kevin J. Pridham
Fralin Biomedical Research Institute at VTC, Roanoke, VA 24016, USA
Kasen R. Hutchings
Fralin Biomedical Research Institute at VTC, Roanoke, VA 24016, USA; Department of Internal Medicine, Virginia Tech Carilion School of Medicine, Roanoke, VA 24016, USA
Patrick Beck
Fralin Biomedical Research Institute at VTC, Roanoke, VA 24016, USA; Department of Internal Medicine, Virginia Tech Carilion School of Medicine, Roanoke, VA 24016, USA
Min Liu
Fralin Biomedical Research Institute at VTC, Roanoke, VA 24016, USA
Eileen Xu
Fralin Biomedical Research Institute at VTC, Roanoke, VA 24016, USA; Department of Internal Medicine, Virginia Tech Carilion School of Medicine, Roanoke, VA 24016, USA
Erin Saechin
Fralin Biomedical Research Institute at VTC, Roanoke, VA 24016, USA; Department of Internal Medicine, Virginia Tech Carilion School of Medicine, Roanoke, VA 24016, USA
Vincent Bui
Fralin Biomedical Research Institute at VTC, Roanoke, VA 24016, USA
Chinkal Patel
Fralin Biomedical Research Institute at VTC, Roanoke, VA 24016, USA
Jamie Solis
Fralin Biomedical Research Institute at VTC, Roanoke, VA 24016, USA
Leah Huang
Fralin Biomedical Research Institute at VTC, Roanoke, VA 24016, USA
Allison Tegge
Fralin Biomedical Research Institute at VTC, Roanoke, VA 24016, USA
Deborah F. Kelly
Department of Biomedical Engineering, Pennsylvania State University, University Park, PA 16802, USA; Huck Institutes of the Life Sciences, Pennsylvania State University, University Park, PA 16802, USA; Center for Structural Oncology, Pennsylvania State University, University Park, PA 16802, USA
Zhi Sheng
Fralin Biomedical Research Institute at VTC, Roanoke, VA 24016, USA; Department of Biomedical Engineering, Pennsylvania State University, University Park, PA 16802, USA; Faculty of Health Science, Virginia Tech, Blacksburg, VA 24061, USA; Corresponding author
Summary: 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/β/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 PI3Kβ being the highest. Patients deficient of O6-methylguanine-DNA-methyltransferase (MGMT) and expressing elevated levels of PI3Kβ, defined as MGMT-deficient/PI3Kβ-high, were less responsive to temozolomide and experienced poor prognosis. Consistently, MGMT-deficient/PI3Kβ-high glioblastoma cells were resistant to temozolomide. Perturbation of PI3Kβ, but not other kinases, sensitized MGMT-deficient/PI3Kβ-high glioblastoma cells or tumors to temozolomide. Moreover, PI3Kβ-selective inhibitors and temozolomide synergistically mitigated the growth of glioblastoma stem cells. Our results have demonstrated an essential role of PI3Kβ in chemoresistance, making PI3Kβ-selective blockade an effective chemosensitizer for glioblastoma.
