Biological and metabolic effects of IACS-010759, an OxPhos inhibitor, on chronic lymphocytic leukemia cells

Abstract

// Hima V. Vangapandu 1 , Brandon Alston 1 , Joshua Morse 1 , Mary L. Ayres 1 , William G. Wierda 2 , Michael J. Keating 2 , Joseph R. Marszalek 3 and Varsha Gandhi 1, 2 1 Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA 2 Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA 3 Institute of Applied Cancer Science and the Center for Co-Clinical Trials, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA Correspondence to: Varsha Gandhi, email: vgandhi@mdanderson.org Keywords: mitochondria; IACS-010759; metabolism; 2-dG; OxPhos Received: August 14, 2017      Accepted: January 09, 2018      Published: May 18, 2018 ABSTRACT Blood cells from patients with chronic lymphocytic leukemia (CLL) are replicationally quiescent but transcriptionally, translationally, and metabolically active. Recently, we demonstrated that oxidative phosphorylation (OxPhos) is a predominant pathway in CLL for energy production and is further augmented in the presence of the stromal microenvironment. Importantly, CLL cells from patients with poor prognostic markers showed increased OxPhos. From these data, we theorized that OxPhos can be targeted to treat CLL. IACS-010759, currently in clinical development, is a small-molecule, orally bioavailable OxPhos inhibitor that targets mitochondrial complex I. Treatment of primary CLL cells with IACS-010759 greatly inhibited OxPhos but caused only minor cell death at 24 and 48 h. In the presence of stroma, the drug successfully inhibited OxPhos and diminished intracellular ribonucleotide pools. However, glycolysis and glucose uptake were induced as compensatory mechanisms. To mitigate the upregulated glycolytic flux, we used 2-deoxy-D-glucose in combination with IACS-010759. This combination reduced both OxPhos and glycolysis and induced cell death. Consistent with these data, low-glucose culture conditions sensitized CLL cells to IACS-010759. Collectively, these data suggest that CLL cells adapt to use a different metabolic pathway when OxPhos is inhibited and that targeting both OxPhos and glycolysis pathways is necessary for biological effect.