objective: Treatment paradigms for Isocitrate dehydrogenase (IDH) mutant gliomas are rapidly evolving. While typically indolent and responsive to initial treatment, these tumors invariably recur at higher grade and require salvage treatment. Homozygous deletion of the tumor suppressor gene CDKN2A/B frequently emerges at recurrence in these tumors, driving poor patient outcome. We investigated the effect of CDK-Rb pathway blockade on IDH-mutant glioma growth in vitro and in vivo using CDK4/6 inhibitors (CDKi).
methods: Cell viability, proliferation assays and flow cytometry were used to examine the pharmacologic effect of two distinct CDKis, palbociclib and abemaciclib, in multiple patient-derived IDH-mutant gli... More
objective: Treatment paradigms for Isocitrate dehydrogenase (IDH) mutant gliomas are rapidly evolving. While typically indolent and responsive to initial treatment, these tumors invariably recur at higher grade and require salvage treatment. Homozygous deletion of the tumor suppressor gene CDKN2A/B frequently emerges at recurrence in these tumors, driving poor patient outcome. We investigated the effect of CDK-Rb pathway blockade on IDH-mutant glioma growth in vitro and in vivo using CDK4/6 inhibitors (CDKi).
methods: Cell viability, proliferation assays and flow cytometry were used to examine the pharmacologic effect of two distinct CDKis, palbociclib and abemaciclib, in multiple patient-derived IDH-mutant glioma lines. Isogenic models were used to directly investigate the influence of CDKN2A/B status on CDKi sensitivity. Orthotopic xenograft tumor models were used to examine efficacy and tolerability of CDKi in vivo.
results: CDKi treatment leads to decreased cell viability and proliferative capacity in patient-derived IDH-mutant glioma lines, coupled with enrichment of cells in G1 phase. CDKN2A inactivation sensitizes IDH-mutant glioma to CDKi in both endogenous and isogenic models with engineered CDKN2A deletion. CDK4/6 inhibitor administration improves survival in orthotopically implanted IDH-mutant glioma models.
conclusions: IDH-mutant gliomas with deletion of CDKN2A/B are sensitized to CDK4/6 inhibitors. These results support investigation of the use of these agents in a clinical setting.
