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

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.

Utilizing Synergistic Potential of Mitochondria-Targeting Drugs for Leukemia Therapy

“…Interestingly, both IACS/VIN and RT/2-DG combinations significantly enhanced ECAR (extracellular acidification rate) by 27-234% in MOLM-13 cells and studied patient samples (n = 5/6), as well as in PBMCs in case of IACS/VIN (Table S8). Previous reports have shown that inhibiting Complex I of the ETC with IACS-010759 or rotenone upregulates glucose consumption and glycolysis (42,43). As expected, normalized coupling efficiency was also significantly associated (r = 0.786, p < 0.001) with ATP-linked OCR ( Figure 7E).…”

“…IACS-010759, which is currently in clinical development, is a novel OxPhos inhibitor that targets mitochondrial complex I (35). This compound caused only minor cell death of chronic lymphocytic leukemia at 24 h of treatment, but the addition of 2-deoxy-D-glucose significantly increased cytotoxicity (43). Here we demonstrate that the combination of IACS-010759 and vinorelbine impairs several mitochondrial functions, such as oxygen consumption and coupling efficiency.…”

Targeting Metabolism in Cancer Cells and the Tumour Microenvironment for Cancer Therapy

“…At present, the prevailing plasticity of the metabolic circuitry is thought to be the greatest limiting factor in the success of metabolic inhibition, rendering the singular targeting of metabolic pathways ineffective. Dual metabolic inhibition is a promising strategy to overcome this, especially combinations involving the inhibition of glycolysis and OXPHOS, or glycolysis and glutaminolysis [ 185 , 223 , 230 , 231 , 233 ]. Though supported by robust preclinical data, the clinical evaluation of dual metabolic inhibitor strategies remain in their infancy stages [ 286 ].…”

“…Another complex I inhibitor, IACS-010759, recently demonstrated preclinical efficacy in inhibiting growth of CLL and acute myeloid leukaemia (AML) [ 185 ]. IACS-010759 is potent and can be administered orally, and has progressed to phase I trials in advanced solid tumours, which was reported to be well-tolerated with preliminary evidence of anti-tumour activity.…”

“…Moreover, treatment of OXPHOS-competent hereditary leiomyomatosis RCC with the complex I inhibitor IACS-010759 plus simultaneous inhibition of the glycolytic enzyme phosphogluconate dehydrogenase (PGD) led to synthetic lethality [ 231 ]. Likewise in CLL cells, simultaneous inhibition of OXPHOS by IACS-010759 and glycolysis by 2-DG had a more pronounced effect than either inhibitor alone, providing a strong biological rationale for dual metabolic inhibition to deprive cancer cells of ATP [ 185 ].…”