CDK6 kinase inhibition unmasks metabolic dependencies in BCR::ABL1+ leukemia

Metabolic reprogramming and cell cycle deregulation are hallmarks of cancer cells. The cell cycle kinase CDK6 has recently been implicated in a wide range of hematopoietic malignancies. We here investigate the role of CDK6 in the regulation of cellular metabolism in BCR::ABL1+ leukemic cells. Our study, using gene expression data and ChIP-Seq analysis, highlights the contribution of CDK6 kinase activity in the regulation of oxidative phosphorylation. Our findings imply a competition for promoter interaction of CDK6 with the master regulator of mitochondrial respiration, NRF-1. In line, cells lacking kinase active CDK6 display altered mitochondria morphology with a defective electron transport chain. The enhanced cytoplasm/mitochondria ATP ratio paralleled by high pyruvate and lactate levels indicate a metabolic switch to glycolysis. Accordingly, combinatorial treatment of leukemic cells including imatinib resistant cells with the CDK4/6 inhibitor palbociclib and the glycolysis inhibitor 2-deoxyglucose (2-DG) enhanced apoptosis, while blocking cell proliferation in leukemic cells. These data may open a new therapeutic avenue for hematologic malignancies with high CDK6 expression by exploiting metabolic vulnerabilities unmasked by blocking CDK6 kinase activity that might even be able to overcome imatinib resistance.

Keywords (eng)

HumansCyclin-Dependent Kinase 6 MetabolismCyclin-Dependent Kinase 6 Antagonists & InhibitorsFusion Proteins, bcr-abl GeneticsFusion Proteins, bcr-abl MetabolismGlycolysisdrug EffectsProtein Kinase Inhibitors PharmacologyPiperazines PharmacologyCell Line, TumorMitochondria MetabolismMitochondria Drug EffectsApoptosisdrug EffectsOxidative Phosphorylation Drug EffectsCell ProliferationCell Drug EffectsDeoxy GlucoseDeoxy PharmacologyPyridines PharmacologyLeukemia, Myelogenous, Chronic, BCR-ABL Positive MetabolismLeukemia, Myelogenous, Chronic, BCR-ABL Positive Drug TherapyLeukemia, Myelogenous, Chronic, BCR-ABL Positive PathologyLeukemia, Myelogenous, Chronic, BCR-ABL Positive GeneticsImatinib Mesylate PharmacologyImatinib Mesylate Therapeutic UseDrug Resistance, Neoplasm Drug EffectsK562 Cells

Type (eng)

journal article

Language

[eng]

Persistent identifier

https://phaidra.vetmeduni.ac.at/o:3977

DOI

10.1038/s41419-025-07434-1

Is in series

Title (eng)

Cell Death & Diseases

Volume