Complex I inhibitor of oxidative phosphorylation in advanced solid tumors and acute myeloid leukemia: phase I trials

Abstract

While targeting oxidative phosphorylation (OXPHOS) is a rational anticancer strategy, patient bene t with OXPHOS inhibitors in the clinic has yet to be achieved. Based on promising preclinical data, we advanced IACS-010759, a highly potent and selective small-molecule inhibitor of mitochondrial complex I, into two phase I trials in patients with acute myeloid leukemia (NCT02882321) or advanced solid tumors (NCT03291938). Clinical ndings revealed that IACS-010759 had a narrow therapeutic index with emergent dose-limiting toxicities that included elevated blood lactate and neurotoxicity, obstructing efforts to maintain target plasma exposure. Consequently, only modest on-target inhibition and limited antitumor activity were observed. Follow-up reverse translational studies uncovered that IACS-010759 reduced oxygen consumption rates in neurons and damaged myelin. Further, IACS-010759-treated mice displayed behaviors indictive of neuropathy, which were minimized with the co-administration of a histone deacetylase 6 inhibitor. Our ndings urge caution in the continued development of complex I inhibitors as antitumor agents.

Mitochondrial metabolism in primary and metastatic human kidney cancers

“…But the ETC also supports the maintenance of a favorable redox balance, ubiquinol oxidation, and production of anabolic precursors, all of which support tumour growth in various contexts 58–61 . Potent, systemic blockade of the ETC in patients results in dose-limiting toxicities 62 , but it may be possible to widen the therapeutic window by tailoring therapies to selectively target the most relevant aspects of mitochondrial function.…”

“…But the ETC also supports the maintenance of a favorable redox balance, ubiquinol oxidation, and production of anabolic precursors, all of which support tumour growth in various contexts [58][59][60][61] . Potent, systemic blockade of the ETC in patients results in dose-limiting toxicities 62 , but it may be possible to widen the therapeutic window by tailoring therapies to selectively target the most relevant aspects of mitochondrial function. were enrolled on protocol STU2019-1061 and were infused at the following rate: primer dose for 5 minutes at a rate of 0.6 mg/kg/minute, followed by a continuous infusion of 5.0 μmol/kg/minute (0.73 mg/kg/minute).…”

Mitochondrial redox adaptations enable alternative aspartate synthesis in SDH-deficient cells

“…On the contrary, CI inhibitors have also been identified as a therapeutic avenue for cancer treatment, which can decrease tumor growth by affecting redox homeostasis and suppressing intratumoral aspartate ( Baccelli et al, 2019 ; Gui et al, 2016 ; Martínez-Reyes et al, 2020 ; Molina et al, 2018 ; Sullivan et al, 2018 ; Wheaton et al, 2014 ). Notably, the responses to these mitochondrial inhibitors have been variable across clinical trials and cancer models suggesting that heterogeneity in mitochondrial metabolism may govern the responses to CI inhibitors, and potentially to future inhibitors of reductive mitochondrial anabolism ( Janku et al, 2021 ; Momcilovic et al, 2019 ; Yap et al, 2019 ; Yap et al, 2023 ). Thus, understanding mitochondrial phenotypes will be critical for leveraging cancer cell metabolic changes to improve cancer therapy.…”

MYC-driven increases in mitochondrial DNA copy number occur early and persist throughout prostatic cancer progression

“…For example, increased mtDNA copy number has been described in acute myelogenous leukemia (AML) (36, 37), endometrial carcinoma (38), esophageal squamous cancer (39), pancreatic cancer (5), and colorectal cancer (40). Further, treatment with an inhibitor of mtDNA replication (41) or of a mitochondrial complex 1 inhibitor (42) in AML has shown promise in preclinical studies. Notably, increased mtDNA content was mechanistically linked to microsatellite-stable colorectal cancer cell proliferation and metastasis (40).…”