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Peer-reviewedCC BY 4.0Cancers

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

  • Ankush Chandra1,2
  • Mariana K. Najjar1,2,3
  • Phi-Long Tran1,2
  • Joshua Cha1,2
  • Marc Morales1,4
  • Hui-Wen Lo1,2,3
4 affiliations
  1. 1Vivian L. Smith Department of Neurosurgery, McGovern Medical School, The University of Texas Health Houston, Houston, TX 77030, USA
  2. 2Department of Cell Biology and Genetics, College of Medicine, Texas A&M University, College Station, TX 77843, USA
  3. 3Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
  4. 4Department of Neurology, Virginia Tech Carilion, Roanoke, VA 24016, USA
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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.

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Cite

BibTeXRIS
BibTeX
@article{chandra2026cyclindependent,
  title = {{Cyclin-Dependent Kinases 4/6 Inhibition in Glioblastoma: From Molecular Rationale to Therapeutic Challenges and Opportunities}},
  author = {Ankush Chandra and Mariana K. Najjar and Phi-Long Tran and Joshua Cha and Marc Morales and Hui-Wen Lo},
  journal = {Cancers},
  year = {2026},
  month = nov,
  doi = {10.3390/cancers18213578},
  url = {https://www.mdpi.com/2072-6694/18/21/3578},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Cyclin-Dependent Kinases 4/6 Inhibition in Glioblastoma: From Molecular Rationale to Therapeutic Challenges and Opportunities
AU  - Ankush Chandra
AU  - Mariana K. Najjar
AU  - Phi-Long Tran
AU  - Joshua Cha
AU  - Marc Morales
AU  - Hui-Wen Lo
PY  - 2026
DA  - 2026/11/06
JO  - Cancers
DO  - 10.3390/cancers18213578
UR  - https://www.mdpi.com/2072-6694/18/21/3578
AB  - 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.
SN  - 2072-6694
ER  -