Abstract
Cyclin-dependent kinases (CDKs) are important regulatory enzymes in the normal physiological processes that drive cell-cycle transitions and regulate transcription. Virtually all cancers harbour genomic alterations that lead to the constitutive activation of CDKs, resulting in the proliferation of cancer cells. CDK inhibitors (CKIs) are currently in clinical use for the treatment of breast cancer, combined with endocrine therapy. In this review, we describe the potential of CKIs for the treatment of cancer with specific focus on glioblastoma (GBM), the most common and aggressive primary brain tumour in adults. Despite intense effort to combat GBM with surgery, radiation and temozolomide chemotherapy, the median survival for patients is 15 months and the majority of patients experience disease recurrence within 6-8 months of treatment onset. Novel therapeutic approaches are urgently needed for both newly diagnosed and recurrent GBM patients. In this review, we summarise the current preclinical and clinical findings emphasising that CKIs could represent an exciting novel approach for GBM treatment.
Highlights
Cyclin-dependent kinases (CDKs) are a family of enzymes-serine threonine kinases - that, under normal physiological conditions, play significant roles in controlling cell-cycle progression and transcription regulation[1]
A recent publication showed the potential of palbociclib combined with RT in patient-derived glioblastoma cell lines[115]. Despite these promising results obtained in preclinical studies, palbociclib was inefficient when tested as a monotherapy in a Phase II clinical trial for recurrent GBM patients with detectable retinoblastoma protein (Rb) expression (NCT01227434)[11]
The location of brain tumours and their protection by the blood-brain barrier (BBB) means that brain tumours remain the most challenging malignancies to treat
Summary
Cyclin-dependent kinases (CDKs) are a family of enzymes-serine threonine kinases - that, under normal physiological conditions, play significant roles in controlling cell-cycle progression and transcription regulation[1]. Recent studies showed that the treatment resistance evident in GBM can be overcome by using drugs targeting the expression of anti-apoptotic proteins and those that target cell-cycle dysregulation[39], including but not limited to, CDK4/6/cyclin D overexpression. The essential roles of CDKs in the intracellular control of the cell cycle and regulation of transcription and DNA repair[79] make them highly suitable as targets of inhibitors for the treatment of cancer.
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