Cyclin-Dependent Kinases 4/6 Inhibition in Glioblastoma: From Molecular Rationale to Therapeutic Challenges and Opportunities

Abstract

Glioblastoma (GBM) remains the most lethal primary malignant brain tumor in adults despite maximal resection, radiotherapy, and temozolomide. The cyclin D-CDK4/6-RB axis plays a significant role in cell cycle regulation and is amongst the most frequently dysregulated pathways in many cancers including GBM, thus providing a strong rationale for using CDK4/6 inhibitors (CDK4/6is) in treating this tumor. While palbociclib, ribociclib, and abemaciclib are FDA-approved to treat hormone positive breast cancer, they have demonstrated robust target engagement and efficacy in preclinical studies in GBM. However, clinical trial data has been modest, highlighting a major gap between biological rationale and therapeutic efficacy in the clinical setting. In this comprehensive review, we examine the molecular functions of CDK4/6 in GBM, delve into the pharmacologic properties of approved and emerging inhibitors, explore mechanisms of drug resistance and discuss combination strategies, clinical experience till date, and potential biomarkers for ideal patient selection. Future progress will likely require CNS-active inhibitors, rational combination therapies, functional biomarker selection, and early confirmation of adequate tumor drug exposure and pathway suppression.