In light of the disappointing termination of clinical trials with potent complex I inhibitors, such as IACS-010759, justification for oxidative phosphorylation inhibitors and mitochondrial targeting strategies has been called into question. Consideration of these agents’ potency, tissue selectivity and toxicity demonstrate what lessons can be learned from this failure and where new opportunities lie.
The field of cancer metabolism has evolved greatly over the last 100 years, from the seminal discovery of aerobic glycolysis in tumours to more recent evidence that respiration is not inconsequential and is frequently enhanced in cancer. More specifically, as dependencies on oxidative phosphorylation (OXPHOS) appear prevalent in a variety of aggressive cancer types, the development of OXPHOS inhibitors through targeting the electron transport chain has shown promising pre-clinical efficacy [1]. However, termination of clinical trials in oncology utilising electron transport chain complex I selective inhibitors BAY87-2243, ASP4132, and most recently IACS-010759, due to dose-limiting toxicities, has raised questions on the clinical viability of such approaches [2,3,4].
IACS-010759 was developed as a highly potent complex I inhibitor and demonstrated promising anti-cancer efficacy in multiple animal models within a moderate safety window. However, Yap et al. have carefully reported the results of two phase I clinical trials of IACS-010759 in patients with advanced solid tumours (23 patients), some with OXPHOS sensitive mutations, and refractory acute myeloid leukaemia (AML) (17 patients). IACS-010759 had unacceptable toxicities including elevated blood lactate, lactic acidosis, vomiting, and peripheral neuropathy; resulting in early trial termination [4]. Dose-related toxicities prohibited maintenance of target plasma levels, with only 1 patient achieving a partial response.
The extremely narrow, if any, therapeutic window of IACS-010759, is likely attributed to its highly potent, on-target complex I inhibition, which operates on a nanomolar range in vitro, similar to toxins targeting complex I e.g., rotenone. Excessive inhibition of mitochondrial respiration is clearly associated with a glycolytic shift towards increased lactate production and lactic acidosis, a common adverse event with IACS-010759. However, other less potent OXPHOS inhibitors such as metformin, nitric oxide and arsenic trioxide, have been widely used in clinics for decades for indications outside of oncology and have established safety profiles [2]. Many moderate OXPHOS inhibitors assessed in oncology clinical trials have demonstrated safe administration and tolerability with other therapies [5]. Moderate OXPHOS inhibitor and antimalarial drug, atovaquone, which specifically targets complex III, produced an anti-cancer effect in vitro at clinically achievable plasma concentrations and retrospective analysis in AML patients correlated higher atovaquone dosing with lower relapse rates [6]. Additionally, the metabolic plasticity of cancers may limit the therapeutic window of OXPHOS inhibitors as monotherapies, but their use in combination therapies, specifically to target cancer stem cells and chemotherapy resistant cancers has been evaluated extensively preclinically. Treatment with complex I inhibitor OPB-51602 demonstrated re-sensitisation to tyrosine kinase inhibitors in vitro, and also resulted in significant tumour regression and metabolic responses in patients with secondary resistance to epidermal growth factor receptor inhibitors in a phase 1 trial [7].
The clinical applications of OXPHOS inhibitors can extend beyond anti-proliferative chemotherapies. Tumour hypoxia, which results from an imbalance between oxygen demand and delivery within the chaotic vasculature of solid malignancies, is strongly implicated in radiation therapy resistance. Modest reductions in cellular oxygen consumption, modelled to be approximately 30% can increase local oxygen availability in tumours to alleviate hypoxia and improve radiosensitivity [8]. Reducing cellular oxygen consumption can be achieved through inhibition of the electron transport chain and several moderate OXPHOS inhibitors have demonstrated tumour reoxygenation and metabolic radiosensitization in preclinical models (Fig. 1a), including papaverine, an antispasmodic drug found to also inhibit complex I [9]. Such strategies would require adequate drug levels in tumours and a subsequent hypoxia modifying effect only at the time of radiation and this can be achieved with moderate OXPHOS inhibition. In non-small cell lung cancer (NSCLC) patients, atovaquone delivered at standard oral doses demonstrated significant increases in tumour reoxygenation [10]. This study clearly demonstrated OXPHOS inhibition resulted in a pharmacodynamic effect achieved within a safe clinical window. Clinical trials in NSCLC patients assessing the efficacy of the combination of atovaquone or papaverine with either chemoradiotherapy or stereotactic body radiotherapy are ongoing (NCT04648033, NCT03824327, NCT05136846).
Increasing the differential biological effect a drug has on its target tissue is another strategy that can improve therapeutic benefit without exacerbating healthy tissue toxicity. Drug design strategies to mitigate this can include the addition of mitochondria targeting moieties, such as triphenylphosphine (TPP+). TPP+ is a lipophilic molecule that possesses delocalised cations enabling its accumulation in the mitochondria matrix according to the charge differential across the plasma and mitochondria membranes – see Fig. 1b [11]. More importantly, the mitochondrial membrane potential has been documented to be substantially higher in tumour cells than normal tissue and is associated with a more invasive cellular phenotype, thus selectively rendering tumour cells more susceptible to drug accumulation with TPP+ conjugates [11]. Gamitrinib, a TPP+ conjugate of a heat shock protein-90 inhibitor, has demonstrated improved pharmacokinetics compared to its parent compound and possesses a safety profile in rats and dogs several fold greater than its effective doses in mice [12]. A phase I clinical trial of gamitrinib in advanced solid tumours is ongoing and will provide insight to how the addition of tumour mitochondria targeting strategies may improve therapeutic outcomes (NCT04827810). In a lung carcinoma model, tumour heterogeneity of TPP+ uptake was also observed, demonstrating that total tumour targeting may not be achieved solely by this strategy [13]. However, metabolic radiosensitizers do not require OXPHOS inhibition in all regions of a tumour to observe hypoxia modulation, indicating that TPP+ based agents can still provide improved safety and therapeutic benefit in this context. Tumour selectivity may also be improved through the use of antibody drug conjugates (ADCs). Several ADCs have been approved and are currently being developed for haematological malignancies, for which OXPHOS dependencies can be frequent [1, 14]. Additionally, ADCs commonly utilise potent drug payloads, which can be leveraged to trial toxic agents originally discarded in early clinical trials or untested as single agents, as seen with the development of Heidelberg Pharma’s alpha amanitin ADC [14]. It will be essential to have pharmacodynamic endpoints in the aforementioned trials, such as metabolic profiles for lactate and mitochondrial effects, repeat biopsies for histology, and imaging scans for hypoxia and its modulation.
While the early termination of IACS-010759 comes as disappointing news in the development of metabolism targeting therapies, there are several ways ahead for selectively targeting mitochondria in cancer. Preclinical toxicology highlights the problems of using different species which have subtle differences in the susceptibility of their mitochondria at a target and tissue level. Considerations for the impact of OXPHOS inhibition on the tumour microenvironment, including proliferation of different types of T-cells, should also be evaluated carefully in the development of new inhibitors. Additional approaches may include organotypic tissue cultures of normal susceptible tissues, tumour organoids, and immunocompetent in vivo models such as genetically engineered mouse models.
References
Ashton TM, Gillies McKenna W, Kunz-Schughart LA, Higgins GS. Oxidative phosphorylation as an emerging target in cancer therapy. Clin Cancer Res. 2018;24:2482–90.
Xu Y, Xue D, Bankhead A, Neamati N. Why all the fuss about oxidative phosphorylation (OXPHOS)? J Med Chem. 2020;63:14276–307.
Janku F, LoRusso P, Mansfield AS, Nanda R, Spira A, Wang T, et al. First-in-human evaluation of the novel mitochondrial complex I inhibitor ASP4132 for treatment of cancer. Invest N Drugs. 2021;39:1348–56.
Yap TA, Daver N, Mahendra M, Zhang J, Kamiya-Matsuoka C, Meric-Bernstam F, et al. Complex I inhibitor of oxidative phosphorylation in advanced solid tumors and acute myeloid leukemia: phase I trials. Nat Med. 2023;29:115–26.
Boreel DF, Span PN, Heskamp S, Adema GJ, Bussink J. Targeting oxidative phosphorylation to increase the efficacy of radio- and immune-combination therapy. Clin Cancer Res. 2021;27:2970–8.
Xiang M, Kim H, Ho VT, Walker SR, Bar-Natan M, Anahtar M, et al. Gene expression-based discovery of atovaquone as a STAT3 inhibitor and anticancer agent. Blood. 2016;128:1845–53.
Hirpara J, Eu JQ, Tan JKM, Wong AL, Clement MV, Kong LR, et al. Metabolic reprogramming of oncogene-addicted cancer cells to OXPHOS as a mechanism of drug resistance. Redox Biol. 2019;25:101076.
Secomb TW, Hsu R, Ong ET, Gross JF, Dewhirst MW. Analysis of the effects of oxygen supply and demand on hypoxic fraction in tumors. Acta Oncol. 1995;34:313–6.
Benej M, Hong X, Vibhute S, Scott S, Wu J, Graves E, et al. Papaverine and its derivatives radiosensitize solid tumors by inhibiting mitochondrial metabolism. Proc Natl Acad Sci USA 2018;115:10756–61.
Skwarski M, McGowan DR, Belcher E, Di Chiara F, Stavroulias D, McCole M, et al. Mitochondrial inhibitor atovaquone increases tumor oxygenation and inhibits hypoxic gene expression in patients with non-small cell lung cancer. Clin Cancer Res. 2021;27:2459–69.
Zielonka J, Joseph J, Sikora A, Hardy M, Ouari O, Vasquez-Vivar J, et al. Mitochondria-targeted triphenylphosphonium-based compounds: syntheses, mechanisms of action, and therapeutic and diagnostic applications. Chem Rev. 2017;117:10043–120.
Hayat U, Elliott GT, Olszanski AJ, Altieri DC. Feasibility and safety of targeting mitochondria for cancer therapy - preclinical characterization of gamitrinib, a first-in-class, mitochondriaL-targeted small molecule Hsp90 inhibitor. Cancer Biol Ther. 2022;23:117–26.
Momcilovic M, Jones A, Bailey ST, Waldmann CM, Li R, Lee JT, et al. In vivo imaging of mitochondrial membrane potential in non-small-cell lung cancer. Nature. 2019;575:380–4.
Dumontet C, Reichert JM, Senter PD, Lambert JM, Beck A. Antibody-drug conjugates come of age in oncology. Nat Rev Drug Discov. 2023;22:641–61. https://doi.org/10.1038/s41573-023-00709-2.
Author information
Authors and Affiliations
Contributions
This work was devised, reviewed, and edited jointly by GSH and ALH. NDM wrote and edited the manuscript and LCH reviewed and edited this work.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
About this article
Cite this article
Machado, N.D., Heather, L.C., Harris, A.L. et al. Targeting mitochondrial oxidative phosphorylation: lessons, advantages, and opportunities. Br J Cancer 129, 897–899 (2023). https://doi.org/10.1038/s41416-023-02394-9
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41416-023-02394-9