Cyclin-dependent kinase inhibitors in head and neck cancer and glioblastoma—backbone or add-on in immune-oncology?

Abstract

Cyclin-dependent kinases (CDK) control the cell cycle and play a crucial role in oncogenesis. Pharmacologic inhibition of CDK has contributed to the recent clinical approval of dual CDK4/6 inhibitors for the treatment of breast and small cell lung cancer. While the anticancer cell effects of CDK inhibitors are well-established, preclinical and early clinical studies describe additional mechanisms of action such as chemo- and radiosensitization or immune stimulation. The latter offers great potential to incorporate CDK inhibitors in immune-based treatments. However, dosing schedules and accurate timing of each combination partner need to be respected to prevent immune escape and resistance. In this review, we provide a detailed summary of CDK inhibitors in the two solid cancer types head and neck cancer and glioblastoma multiforme; it describes the molecular mechanisms of response vs. resistance and covers strategies to avoid resistance by the combination of immunotherapy or targeted therapy.

The Individual Effects of Cyclin-Dependent Kinase Inhibitors on Head and Neck Cancer Cells—A Systematic Analysis

“…For the more global acting CDKi’s, such beneficial responses are very unlikely. Instead, leukopenia and neutropenia were reported as direct consequences of the complex mode of action, including interference with RNA polymerase II binding [ 30 , 31 , 32 ]. These systemic toxicities constitute a major limitation and clinicians will have to cope with this challenge.…”

Translational Insights and New Therapeutic Perspectives in Head and Neck Tumors

“…In the last years, different CDK4/6 inhibitors have been approved for the treatment of breast cancer and have been tested in late-phase trials in other malignancies [78][79][80]. Recently, CDK inhibition has emerged as a potential mechanism of chemo-and radiosensitization and immune stimulation, leading to preclinical and clinical research that incorporates ICIs and CDK inhibitors in different settings [81].…”

“…In HNSCC, beyond CDK4/6 inhibition, other kinases of the same family have been identified as potential biomarkers of response and poor outcome [81,82].…”

“…The majority of HNSCCs show a genomic profile consistent with tobacco exposure or, alternatively, are characterized by detectable HPV DNA. Recently, different data have been published on the mutational landscape of HNSCCs showing frequent alterations in TP53, CDKN2A, PTEN, PIK3CA, and HRAS along with mutations in genes related to squamous differentiation as NOTCH1, IRF6, and TP63 [81].…”

Targeting protein kinases for anti-glioma treatment

“…Cyclin-dependent kinases (CDKs) are involved in the cell cycle and oncogenesis, controlling the G1 restriction point. The CDK4/CDK6-cyclin D1-Rb-p16/ ink4a pathway is frequently dysregulated in glioblastoma [92]. As determined in preclinical research, the CDK4 and CDK6 kinase inhibitor abemaciclib has a potential for treating primary central nervous system tumours including glioblastoma.…”