CDK6 kinase inhibition opens up metabolic dependencies in BCR-ABL+ leukemia

Metabolic reprogramming and cell cycle deregulation are hallmarks of cancer cells. We here investigate the role of the cell cycle kinase CDK6 in the regulation of cellular energetics in BCR-ABL+ leukemia. Gene expression data and ChIP-Seq analysis from murine BCR-ABL+ cell lines expressing kinase-inactive CDK6 or no CDK6 highlight an activating role for the kinase in regulating the oxidative phosphorylation gene set by interacting with respective promoter regions. Our data imply a competition of CDK6 and Nrf-1, a master regulator of genes required for mitochondrial respiration, at the same sites. In line, cells expressing kinase- inactive CDK6 show signs of a defective electron transport chain and morphologically changed mitochondria. An enhanced cytoplasm/mitochondria ATP ratio together with high levels of pyruvate and lactate point towards a metabolic switch to glycolysis in those cells. Combinatorial treatment of BCR-ABL+ cell lines with the clinically used CDK4/6 inhibitor palbociclib and the glycolysis inhibitor 2-deoxyglocose (2-DG) reduced proliferation and led to enhanced apoptosis compared to single-agent treatments. Our data, suggest a new therapeutic avenue for hematologic malignancies with high CDK6 expression.