CDK6 kinase inhibition unmasks metabolic dependencies in BCR::ABL1+ leukemia
Lisa Scheiblecker, Thorsten Klampfl, Eszter Doma, Sofie Nebenfuehr, Omar Torres‐Quesada, Sophie Strich, Gerwin Heller, Daniela Werdenich, Waltraud Tschulenk, Markus Zojer, Florian Bellutti, Alessia Schirripa, Sabine Zöchbauer‐Müller, Peter Valent, Ingrid Walter, Eduard Stefan, Veronika Sexl, Karoline Kollmann
Abstract
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.