RDNA-11. OVERCOMING RADIATION RESISTANCE IN MENINGIOMA: THE EMERGING ROLE OF CDK4/6 INHIBITOR

Abstract Meningiomas are common intracranial brain tumors. Despite surgery and/or radiation therapy, recurrence rates occur in approximately 8–10 % of tumors. This may be due to the dysregulation of the cyclin D and cyclin-dependent kinase (CDK) pathway in malignant meningioma cells and radiation-resistant meningioma cells. The cyclin D-cyclin-dependent kinases 4 and 6 (CDK4/6)-retinoblastoma (Rb) pathway controls the cell cycle restriction point, and is commonly dysregulated in meningioma; making it a rational target for antimeningioma therapy. In this study, we interrogated the capacity of a CDK4/6 inhibitor, palbociclib, to activate RB function against Rb+ meningiomas cells in vitro, ex vivo and in vivo xenograft model. Meningioma tumors in SCID mice treated daily with intraperitoneal injections of palbociclib for 14 days dose dependly with X ray irradiation. Treatment effects were examined by immunoblot, cell viability, apoptosis, and cell cycle progression. Radiation resistance BENMEN1 cells were developed after exposure to repeated 320 kV X ray irradiation. Since CDK4 and CDK6 are proteins that are major part of a cell cycle regulatory pathway in meningioma that also includes p16, cyclin D, and the retinoblastoma (Rb) protein, we analyzed those parameters. Our both in vitro and in vivo data clearly demonstrate that pallbociclib (CDK 4/6 inhibitor) treatment reduced proliferation and has additional effects on cell cycling, including induction of an RB-associated G(1) arrest against Rb+ malignant meningioma cells and radiation-resistant meningioma cells. We did not see any significant effect of palbociclib on Rb – meningima cells. Our results also demonstrated that palbociclib treatment inhibits CDK4 and CDK6 expression and also decreases E2F target gene expression (CCNA2 and CCNE2). All together, our results provide strong evidence that palbociclib can be applied to Rb+ meningiomas as a therapeutic agent.