1. CDKN2A/B Homozygous Deletion Sensitizes IDH-Mutant Glioma to CDK4/6 Inhibition.
- Author
-
Nasser AM, Melamed L, Wetzel EA, Chang JC, Nagashima H, Kitagawa Y, Muzyka L, Wakimoto H, Cahill DP, and Miller JJ
- Subjects
- Humans, Animals, Mice, Cell Line, Tumor, Gene Deletion, Brain Neoplasms genetics, Brain Neoplasms drug therapy, Brain Neoplasms pathology, Homozygote, Cyclin-Dependent Kinase 4 antagonists & inhibitors, Cyclin-Dependent Kinase 4 genetics, Cyclin-Dependent Kinase 6 antagonists & inhibitors, Cyclin-Dependent Kinase 6 genetics, Glioma genetics, Glioma drug therapy, Glioma pathology, Cyclin-Dependent Kinase Inhibitor p16 genetics, Isocitrate Dehydrogenase genetics, Isocitrate Dehydrogenase antagonists & inhibitors, Xenograft Model Antitumor Assays, Benzimidazoles pharmacology, Cyclin-Dependent Kinase Inhibitor p15 genetics, Aminopyridines pharmacology, Mutation, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors therapeutic use, Piperazines pharmacology, Piperazines therapeutic use, Cell Proliferation drug effects, Pyridines pharmacology, Pyridines therapeutic use
- Abstract
Purpose: Treatment paradigms for isocitrate dehydrogenase (IDH)-mutant gliomas are rapidly evolving. Although typically indolent and responsive to initial treatment, these tumors invariably recur at a 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 outcomes. We investigated the effect of CDK-Rb pathway blockade on IDH-mutant glioma growth in vitro and in vivo using CDK4/6 inhibitors (CDKi)., Experimental Design: Cell viability, proliferation assays, and flow cytometry were used to examine the pharmacologic effect of two distinct CDKi, 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 the 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 the 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 the investigation of the use of these agents in a clinical setting., (©2024 American Association for Cancer Research.)
- Published
- 2024
- Full Text
- View/download PDF