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Preclinical Evaluation of the Efficacy of a Cyclin-dependent Kinase Inhibitor Ribociclib in Combination with Letrozole Against Patient-Derived Glioblastoma Cells

ABSTRACT: Ongoing studies suggest that letrozole (LTZ), a drug used in the treatment of breast cancer, can potentially be repurposed as a novel therapeutic for Glioblastoma (GBM). In a phase 0/1 trial in recurrent GBM patients we observed that LTZ permeates into the GBM tissue and triggers dose-dependent changes in the expression of genes regulating cell cycle (e.g. CDKN2A/N2B, CDK4). Based on these observations, we hypothesized that a combination of cyclin dependent kinase (CDK) 4/6 inhibitors with LTZ may result in synergistic anti-GBM activity. Therefore, we assessed the anti-tumor effects of LTZ in combination with ribociclib, a third-generation CDK4/6 inhibitor and the brain pharmacokinetics of ribociclib. Using cell viability and neurosphere growth assay against a panel of patient-derived GBM lines both compounds were found to be cytotoxic when used as single agents and were strongly synergistic when used in combination. We then assessed the DNA damaging effects (ɣH2AX induction), cell cycle arrest and the induction of apoptosis (Annexin V-FITC/PI) of both compounds as single agents and when used in combination. LTZ potentiated ribociclib-induced DNA damage and cell cycle arrest leading to apoptosis. Systemic and brain pharmacokinetics analysis of ribociclib in Sprague-Dawley (SD) rats by serial blood and brain extracellular fluid (ECF) sampling showed that ribociclib penetrates the blood-brain barrier with a partitioning coefficient (Kpu, u, brain) of about 10%. Overall, our studies suggest that a combination of ribociclib with LTZ is likely to be strongly synergistic against GBM at concentrations of the drugs that can be achieved in the brain

ORGANISM(S): Homo sapiens

PROVIDER: GSE301688 | GEO | 2025/09/05

REPOSITORIES: GEO

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Project description:Background: Few druggable targets have been discovered in glioblastoma (GBM); however, increasing knowledge has uncovered two hallmarks of this disease: epigenetic modifications and cell cycle dysregulation. Methods: Here, we investigated the effects of the EZH2 inhibitor GSK126 alone and in combination with the CDK4/6 inhibitor abemaciclib on morphology, growth, invasiveness, protein and gene expression, mitochondrial function, and induction of cell death in patient-derived GBM cells (GBM03, GBM06, GBM14, and GBM15). Results: EZH2 expression, CDK4 amplification, and CDKN2A deletion were first confirmed. The combined use of GSK126 and abemaciclib resulted in synergistic effects in all patient-derived GBM cell lines. After treatment, the cells appeared swollen with a large flat cytoplasm and cellular stress fibers due to HIF1 upregulation and CalR translocation. Notably, abemaciclib-induced cellular stemness (NANOG+, OCT3/4+, and SOX2+) was antagonized by this combination treatment. The MitoStress Test revealed a massive impairment of mitochondrial function. The basal oxygen consumption rate, ATP synthesis, and maximal respiration of the mitochondria decreased, confirming reduced cellular fitness and disrupted endoplasmic reticulum-mitochondrial homeostasis. This was paralleled by massive mitochondrial ROS production leading to mitochondrial depolarization and upregulation of the UPR sensors PERK, ATF6, and IRE1. Spheroid invasion was reduced in 3/4 cases, again with synergistic effects after dual EZH2 and CDK4/6 blockade. Differentially expressed genes involved mitotic aberrations/spindle assembly (Rb, PLK1, RRM2, PRC1, CENPF, TPX2), histone modification (HIST1H1B, HIST1H3G), DNA damage/replication stress events (TOP2A, ATF4), immuno-oncology (DEPDC1), and a shift in the stemness profile towards a more differentiated state. Notably, the antitumor effect was partially confirmed in ovo as well as in patient-derived organoids. Conclusions: We propose dual blocking of GBM hallmarks as a potential treatment strategy. Biomarker-driven targeted therapies will hopefully guide the development of more refined treatments.

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Preclinical Evaluation of the Efficacy of a Cyclin-dependent Kinase Inhibitor Ribociclib in Combination with Letrozole Against Patient-Derived Glioblastoma Cells

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