An inhibitor of the mitochondrial respiratory chain exerts synergistic anti‐tumour effects when combined with alkylating agents

BACKGROUND AND PURPOSE: Cancer cells exhibit the Warburg effect, but oxidative phosphorylation (OXPHOS) is also important for cancer cell proliferation. Metabolic reprogramming from glycolysis to OXPHOS is one mechanism of resistance to anti-tumour drugs. Here, we have synthesized and characterized OPB-111077, a novel, first-in-class orally available small-molecule compound, and investigated its anti-tumour activity and therapeutic potential in combination with alkylating agents. EXPERIMENTAL APPROACH: Inhibition of mitochondrial function by OPB-111077 were assessed by measuring the oxygen consumption rate, ATP production and Complex I enzymatic activity. anti-tumour effects were evaluated in human haematological and solid tumour cell lines and in cell line-derived xenograft and lymphoma patient-derived xenograft models. Mechanistic studies included CRISPR screening, metabolomic analyses, and measurements of the oxygen consumption and extracellular acidification rates. Effects of OPB-111077 combined with alkylating agents were also assessed in mice. KEY RESULTS: OPB-111077 inhibited mitochondrial respiratory chain Complex I, suppressed OXPHOS, and exerted anti-tumour effects in several models. OPB-111077 demonstrated synergism with the alkylating agent bendamustine, with simultaneous inhibition of both OXPHOS and glycolysis. Bendamustine reprogrammed cancer cells into an OXPHOS-dominant state, thereby enhancing the efficacy of OPB-111077. CONCLUSION AND IMPLICATIONS: Based on these findings, we propose a novel anticancer therapeutic strategy of combining OXPHOS inhibitors with alkylating agents. OPB-111077 has demonstrated potential in combination therapy and was recently evaluated with bendamustine and rituximab in a Phase 1 clinical trial for patients with relapsed/refractory diffuse large B-cell lymphoma (NCT04049825).